Flavonoids and other constituents of plants from the genus Knema (Myristicaceae) and their pharmacological studies: An updated review

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Flavonoids are a diverse group of natural compounds extensively studied in various research articles. They are widely distributed in the plant kingdom and exhibit various biological activities, including antioxidant, antiinflammatory, anticancer, antiviral, and antimicrobial effects. The genus Knema Lour., which contains many species in Southeast Asia, has been traditionally used to treat various ailments. The current review aims to provide a comprehensive update on the isolation of flavonoids and other secondary metabolites from the genus Knema Lour. between 1978 and 2022.

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Nội dung Text: Flavonoids and other constituents of plants from the genus Knema (Myristicaceae) and their pharmacological studies: An updated review

Cite this paper: Vietnam J. Chem., 2023, 61(4), 397-411 Minireview DOI: 10.1002/vjch.202200224 Flavonoids and other constituents of plants from the genus Knema (Myristicaceae) and their pharmacological studies: An updated review Abubakar Siddiq Salihu1,2, Wan Mohd Nuzul Hakimi Wan Salleh1* 1 Department of Chemistry, Faculty of Science and Mathematics, Universiti Pendidikan Sultan Idris, 35900 Tanjong Malim, Perak, Malaysia 2 Department of Pure and Industrial Chemistry, Faculty of Natural and Applied Science, Umaru Musa Yar’adua University, Katsina, Nigeria Submitted December 7, 2022; Revised March 9, 2023; Accepted May 28, 2023 Abstract Flavonoids are a diverse group of natural compounds extensively studied in various research articles. They are widely distributed in the plant kingdom and exhibit various biological activities, including antioxidant, anti- inflammatory, anticancer, antiviral, and antimicrobial effects. The genus Knema Lour., which contains many species in Southeast Asia, has been traditionally used to treat various ailments. The current review aims to provide a comprehensive update on the isolation of flavonoids and other secondary metabolites from the genus Knema Lour. between 1978 and 2022. It also discusses the pharmacological studies on these phytochemicals, including their effects on nematodes, bacteria, cytotoxicity, inflammation, and acetylcholinesterase. Through these years, 50 flavonoids have been reported from various species of Knema demonstrating promising pharmacological activities. The information presented in this review can provide a scientific foundation for future research on the possible therapeutic applications of Knema species. It also links the plants’ observed biological effects and traditional uses to their chemical characterization. The data was retrieved from various digital databases, including ScienceDirect, Web of Science, Scopus, Wiley, Taylor and Francis, PubMed, Springer, and Google Scholar. Keywords. Anacardic acids, cytotoxicity, flavonoids, Knema, Myristicaceae. 1. INTRODUCTION neurodegenerative diseases such as Alzheimer's and Parkinson’s.[4] Flavonoids also have anti- Flavonoids are naturally occurring compounds inflammatory properties, which can help to reduce widely distributed in the plant kingdom.[1] They are inflammation throughout the body and improve responsible for the colors of many fruits, vegetables, overall health.[5,6] Other flavonoids have anticancer and flowers and are essential in protecting plants activity, either by inhibiting the growth of cancer from environmental stressors such as UV radiation, cells or by inducing apoptosis (programmed cell pests, and diseases.[2] The main characteristic of death) in cancer cells.[7] Like many other families of flavonoids is their chemical structure, which consists medicinal plants, the Myristicaceae family is of two aromatic rings (A and B) linked by a three- reported to possess bioactive flavonoids. carbon chain that forms a heterocyclic ring (C). The Myristicaceae, a family of arborescent flowering hydroxyl groups attached to the rings and the plants, could be found in wet lowland tropical heterocyclic ring are responsible for the wide range forests. The great ethnobotanical and ecological of biological activities associated with flavonoids. significances of the plants are well-known. The The position and number of these hydroxyl groups Myristicaceae family is one of the 10 most diverse determine the specific type of flavonoids, and more and significant tree families in tropical forests, than 6,000 flavonoids have been identified to date.[3] comprising 500 species and 20 genera.[8] The One of the essential properties of flavonoids is members of this family are evergreen trees or shrubs their antioxidant activity. Flavonoids can scavenge that can grow up to 40 meters tall. Their leaves are free radicals and prevent oxidative damage to cells simple, alternate, and leathery, with a characteristic and tissues. This antioxidant activity has reduced the pungent or spicy scent. The flowers are small and risk of many chronic diseases, including typically unisexual, meaning that each plant bears cardiovascular disease, cancer, and either male or female flowers but not both. These 397 Wiley Online Library © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH
25728288, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202200224 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Wan Mohd Nuzul Hakimi Wan Salleh et al. flowers are usually clustered or arranged in spikes utilized in traditional Thai medicine as a whole-body and are often surrounded by fused bracts at their tonic agent, blood tonic, and anticancer.[17] base. The fruit of Myristicaceae species is a large, Since the late 1970s, plants in the Myristicaceae fleshy drupe containing a single seed. Its shape family have been the focus of comprehensive varies from spherical to ovoid, with a diameter chemical investigations by various research ranging from less than 1 centimeter to over 10 organizations, leading to the isolation of several centimeters. The fruit's outer layer is generally thick compounds from various species of Knema. Based and fibrous, while its inner layer is thin and fleshy. on the studies reviewed, fourteen Knema Lour. A thin, leathery aril usually encloses the seed with a species were the focus of most phytochemical spicy or pungent flavor and bright coloration. In research, which were K. attenuate Warb., K. some species, the aril is separated from the seed and austrosiamensis de Wilde., K. elegans Warb., K. sold as a spice.[9] Among the Asian Myristicaceae, globularia Warb., K. elegans Merr., K. saxalitis de Knema Lour. is the third biggest genus, containing Wilde., K. furfuraceae Warb., K. glauca Warb., K. over 60 Southeast Asian species.[10-14] Tropical laurina Warb., K. hookeriana Warb., K. pachycarpa regions, including Asia, Africa, and Australia, are de Wilde., K. patentinervia de Wilde., K. stellata typical Knema genus (Myristicaceae) habitats. Merr., and K. tenuinervia de Wilde.[19-34] In traditional folk medicine, various parts of the Consequently, the isolation and characterization of Knema species have been used for their medicinal several secondary metabolites, including flavonoids, properties. In India, the bark of K. attenuata Warb. anacardic acid, phenolics, lignans, cardanols, and has been used traditionally to treat various ailments acetophenones, were procured. The substances such as fever, diarrhea, dysentery, and skin exhibited antimicrobial, antioxidant, antiapoptotic, diseases.[15] The bark of K. hookeriana Warb. is used anti-inflammatory, antituberculosis, antiviral, as an astringent and antidiarrheal agent, and the antimalarial, antinematodal, and acetylcholinesterase leaves are used to treat skin diseases.[16] In Sri inhibitory activities.[11,24,25,30,31,33,35] Lanka, the bark of K. globularia Warb. is used to A search on Scopus for the keyword "Knema" treat fever, and the leaves are used for their revealed 1368 citations from 1978 to 2022, antiseptic properties.[17] In Malaysia and Indonesia, indicating the considerable attention this genus has the bark and roots of K. laurina Warb. are used to received in the scientific community. The citations treat fever, malaria, and other infections.[18] The seed were analyzed for the last 15 years (2007-2022) to K. globularia Warb. is used to treat Skin diseases, compare the number of relevant publications on the scabies, and pimples.[19] Moreover, K. corlicosa studied plant species, which showed an increasing Lour. seeds are one of the ingredients in producing trend (figure 1). The high number of citations over medicinal salves.[11] Some plants in the Knema the years suggests a growing interest in the potential species also treat ailments such as jaundice, chronic therapeutic applications of this genus. Further fever, inflammation, spleen disorders, breathing research on the chemical diversity of Knema Lour. disorders, and impaired taste sensations.[12-15] and the bioactivity of its compounds may lead to the Furthermore, K. furfuraceae Warb. is reportedly development of novel drugs for the treatment of various diseases. Figure 1: 15 years Citation overview for researches conducted on genus Knema © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 398
25728288, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202200224 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Flavonoids and other constituents of plants… This article comprehensively reviewed available 2. CHEMICAL CONSTITUENTS AND studies on the phytochemicals and biological PHARMACOLOGICAL STUDIES features of the plants in the genus Knema to understand the usefulness of Knema for plant- 2.1. Flavonoids derived medicines. A computer search of ScienceDirect, Web of Science, Scopus, Wiley, Plants of the Myristicaceae family are good Taylor and Francis, PubMed, Springer, and Google bioactive flavonoid sources. Table 1 summarises the Scholar journal papers was performed (date of isolated flavonoids from the genus Knema. Gonzales access: 10 October 2022, revisited 21 November and co-workers first isolated flavonoids from plants 2022). Subsequently, the bioactive compounds of the genus Knema in 1993, where most flavonoids discovered in Knema plants were drawn with extracted were from the species K. elegans Warb. ChemDraw software. This review aims to compile Investigations on the species' trunk, woods, twigs, and present existing knowledge of plant species to and leaves yielded 32 flavonoids (1–50) (figure 2), enable scientific foundation establishment for future including flavones, isoflavones, flavanones, flavan, research to investigate possible therapeutic and flavonols.[26] applications. Table 1: Flavonoids isolated from the genus Knema No Flavonoids Species Plant part 1 Kenamavoid A K. elegans Twig and leaves[26] 2 Kenamavoid B K. elegans Twig and leaves[26] 3 7,2′-Dihydroxy-6,8-dimethyl-4′,5′- K. elegans Twig and leaves[26] methylenedioxyflavan 4 2′-Hydroxy-7-methoxy-4′,5′- K. elegans Twig and leaves[26] methylenedioxyflavan 5 7-Hydroxy-3′,4′-methylenedioxyflavan K. elegans Twig and leaves[26] 6 Sakuranetin K. elegans Twig and leaves[26] 7 Naringenin K. elegans Twig and leaves[26] 8 Butin K. elegans Twig and leaves[26] 9 Eriodictyol K. elegans Twig and leaves[26] 10 7-Methylliquiritigenin K. elegans Twig and leaves[26] 11 Dihydrokaempferol K. elegans Twig and leaves[26] 12 Kaempferol-3-methyl ether K. elegans Twig and leaves[26] 13 Sulfuretin K. elegans Twig and leaves[26] 14 Knemavone A K. elegans Twig and leaves[27] 15 Knemavone B K. elegans Twig and leaves[27] 16 Virolane K. elegans Twig and leaves[27] 17 1-(2-Hydroxy-4-methoxyphenyl)-3-(4- K. elegans Twig and leaves[27] hydroxy-3-methoxyphenyl)-propane 18 1-(2′,4′-Dihydroxy- K. elegans Twig and leaves[27] 3′-methylphenyl)-3-(2″,-methoxy-4″,5″- methylenedioxyphenyl)-propane 19 Genistein K. elegans Twig and leaves[27] 20 Tectorigenin K. elegans Twig and leaves[27] 21 5,7,2′-Trihydroxy-4′-methoxyisoflavone K. elegans Twig and leaves[27] 22 Formononetin K. elegans Twig and leaves[27] K. glomerata Stem bark[17] 23 2′,5,7-Trihydroxy-4′-metoxyisoflavone K. elegans Twig and leaves[27] 24 7,2′-Dihydroxy-4′,5′- K. elegans Twig and leaves[27] methylenedioxyisoflavone © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 399
25728288, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202200224 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Wan Mohd Nuzul Hakimi Wan Salleh et al. No Flavonoids Species Plant part 25 2′-Hydroxypseudobaptigenin K. elegans Twig and leaves[27] 26 3′,4′,7-Trihydroxyflavone K. elegans Twig and leaves[27] 27 Luteolin K. elegans Twig and leaves[27] K. laurina Stem bark[15] K. saxatilis Leaves[22] 28 Quercetin K. elegans Twig and leaves[27] 29 (2R,4R)-4′-Hydroxy-3′-methyl-6,7- K. elegans Twig and leaves[27] methylenedioxy-4-O-2′-cycloflavan 30 7,4′-Dihydroxy-3′-methoxyjauan K. elegans Twig and leaves[27] 31 (+)-Myristinins A K. elegans Trunk wood[20] K. glauca Leave[23] 32 (+)-Myristinins D K. elegans Trunk wood[20] K. glauca Fruit[23] 33 7,4′-Dihdroxy-4′-methoxyflavanol K. furfuracea Leaves[18] 34 (2S)-3′,4′,7-Trihydroxyflavan K. furfuracea Leaves[18] 35 (2S)-7,3′-Dimethoxy-4′ -hydroxyflavan K. furfuracea Leaves[18] 36 Fisetinidol K. furfuracea Leaves[18] 37 Biochanin A K. furfuracea Stem bark[23] K. globularia Root[9] K. saxatilis Leaves[22] K. glomerata Stem bark[17] 38 7,4′-Dihydroxy-3′-methoxyflavan K. glauca Stem[23] K.austrosiamensis Wood[16] K. laurina Stem bark[15] 39 (+)-Catechin K. laurina Stem bark[15] K. saxatilis Leaves[22] 40 (−)-Catechin K. laurina Stem bark[15] 41 5,7,3′-Trihydroxy-4′-methoxyflavan K. laurina Stem bark[15] 42 2′-Hydroxybiochanin A K. globularia Root[9] 43 2′-Methoxyformononetin K. globularia Root[9] 44 Kaempferol K. saxatilis Leaves[22] 45 3′-O-Methylorobol K. saxatilis Leaves[22] 46 Astragalin K. saxatilis Leaves[22] 47 Isoquercitrin K. saxatilis Leaves[22] 48 Dehydrocatechin A K. saxatilis Leaves[22] 49 Proanthocyanidin A1 K. saxatilis Leaves[22] 50 8-O-Methylretusin K. glomerata Stem bark[17] Zhang et al. extracted 13 flavonoids from the models revealed the remarkable scavenging twigs and leaves of K. elagans, among which activities of 2′-hydroxy-7-methoxy-4′,5′- kenamavoids A (1) and B (2), 7,2′-dihydroxy-6,8- methylenedioxyflavan (4). The report also found that dimethyl-4′,5′-methylenedioxyflavan (3), (2), naringenin (7), and dihydrokaempferol (11) kaempferol-3-methyl ether (12), and sulfuretin (13) were only active in the DPPH model, while (1) and demonstrated moderate inhibitory effects on α- (13) were active in the ABTS model.[36] glycosidase, with IC50 values ranging from 11.80 to Lu et al. obtained 17 flavonoids from the twigs 15.77 μM that was employed to assess primary and leaves of K. elagans, among which two were structure-activity relationships. Moreover, radical novel substances. Among the compounds isolated in scavenging activity evaluations of DPPH and ABTS the study, knemavones A (14) and B (15), virolane © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 400
25728288, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202200224 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Flavonoids and other constituents of plants… (16), 1-(2-hydroxy-4-methoxyphenyl)-3-(4-hydroxy- were isolated from the species. The chalcones 3-methoxyphenyl)-propane (17), and 1-(2′,4′- extracted might serve as potential chemotaxonomic dihydroxy-3′-methylphenyl)-3-(2′′,-methoxy-4′′,5′′- markers for K. elegans Warb. and could be utilized methylenedioxyphenyl)-propane (18) were to distinguish Knema plant species.[37] chalcones, which was the first time the substances R3 OH HO O R4 O HO O R3 HO O R1 O O R4 R2 O O R R1 OH R2 O OH O O 6 R1= OCH3 ; R2 =R3 = OH ; R4 = H 1 R1 = H ; R2 = R4 = OH; R3 = CH3 2 11 R = OH 3 R1 = R3 = CH3 ; R2 = R4 = OH OH 7 R1 = R2 = R3 = OH ; R4 = H 12 R = OCH3 8 R1 = R3 = R4 = OH ; R2 = H 4 R1 = R3 = H ; R2 = OCH3 ; R4 = OH HO O 9 R1 = R2 = R3 = R4 = OH 5 R1 = R3 = R4 = H ; R2 = OH 10 R1 = OCH3 ; R2 = H ; R3 = OH ; R4 = H R1 HO O OH R2 R6 R3 O HO O R2 OH 13 R3 R4 R5 R1 O R4 R1 14 R1=R3=R4=OH; R2=CH3 ; R5=R6= -OCH2O- 19 R1 = R4 = OH ; R2 = R3 = R4 =R5 = H R5 R2 O 15 R1 = R4 = OH ; R2 = H ; R3 = OCH3 ; R5=R6 -OCH2O- 20 R1 = R4 = OH ; R2 = OCH3 ; R3 = R5 = H 26 R1 = R2 = H - 21 R1 = OH ; R2 = R3 = R5 = H ; R4 = OCH3 16 R1 = OH R2 = R4 = H ; R3 = OCH3 ; R5=R6 -OCH2O 27 R1 = H ; R2 = OH 17 R1 = R5 = OH ; R2 = R4 = H ; R3 = OCH3 ; R6=OCH3 22 R1 = R2 = R5 = H ; R3 = OH ; R4 = OCH3 28 R1 = R2 = OH 18 R1 = OH ; R2 = R3 = R4 = OCH3 ; R5=R6 -OCH2O- 23 R1 = R3 = OH; R2 = H ; R4 = OCH3 ; R5 = H 24 R1 = R2 = H ; R3 = OH ; R4 = R5 = -OCH2O- 25 R1 = R3 = OH ; R2 = H ; R4 = R5= -OCH2O- OH 50 R1 = R2 = R3= R5 = H; R4 = OCH3 OH O O HO O OCH3 HO O O OH O OH 29 HO OH HO O HO OH O O OH 30 31 OH 32 OH 7 OH 9 HO O HO O R OH HO O R2 R R3 OH HO O O R1 O R4 33 R = OCH3 35 R = OH 37 R1 = OH ; R2 = R3 = H ; R4 = OCH3 34 R = OH 42 R1 = R2 = OH ; R3 = H ; R4 = OCH3 38 36 R = OCH3 43 R1 = R3 = H ; R2 = R4 = OCH3 45 R1 = R4 = OH ; R2 = H ; R3 = OCH3 OH O OH HO O OH HO O HO O OH HO O OH OH OH OH O OH OH OH OH OH 40 44 OH 39 41 O OH OH OH HO O OH OH OH O R OH O OH O O OH O OH HO O OH O HO OH O HO HO OH OH OH 46 R = H 48 HO 49 47 R = OH Figure 2: Chemical structures of the flavonoids isolated from the genus Knema © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 401
25728288, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202200224 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Wan Mohd Nuzul Hakimi Wan Salleh et al. Deng et al. reported the isolation of two respectively.[39] flavonoids; (+)-myristine A (31) and myristine D K. globularia Warb. has been studied and (32), which exhibited an IC50 of 12.0 and 4.3 µM in screened for phytochemicals, 2ʹ- the presence of bovine serum albumin (BSA) as an methoxyformononetin (43), which was never inhibitor of DNA polymerase and 2.7 and 1.2 µM procured before in the Myristicaceae family, was IC50 in the absence of BSA, making the compounds successfully extracted in the study. The same study the most potent DNA polymerase β inhibitors at the also recorded two other flavonoids, biochanin A (37) time. Both compounds reduced the number of viable and 2ʹ-hydroxybiochanin A (42). Although K. cells by at least 30% when 9 µM was employed for globularia Warb. demonstrated several biological 6 h in an otherwise harmless quantity of bleomycin. activities, but no cytotoxic activities for the isolated The phenomenon was due to the increment of the flavonoids were observed.[19] cytotoxicity of bleomycin on cultured P388D1 cells Similar to K. globularia Warb. and K. saxalitis (75 nM).[30] de Wilde., K. elegans Merr. was possessed the K. saxalitis de Wilde. was reported to possess flavonoid biochanin A (37). Formononetin (22) and nine flavonoids; kaempferol (44), 3′-O-methylorobol 8-O-methylretusin (50) were also procured from the (45), luteolin (27), astragalin (46), (+)-catechin (39), stem barks of K. elegans Merr. in the same study. isoquercitrin (47), dehydrocatechin A (48), The compounds inhibited the growth of crown gall proanthocyanidin A1 (49), and biochanin A (37). tumors on potato tuber discs and exhibited moderate Among the isolated flavonoids, (48) demonstrated but significant toxicity against three human tumor potent antioxidant activities in the cell lines.[27] K. austrosiamensis de Wilde. woods spectrophotometric and chemiluminescence assays. was screened for phytochemicals and isolated one In the study, cytotoxicity assays were also conducted flavonoid, 7,4′-dihydroxy-3′-methoxyflavan (38).[26] in triplicate against Hela, MCF-7, and Hep3B cell In general, flavonoids isolated from different lines, but none of the obtained flavonoids exhibited Knema species possess various bioactivities, such as cytotoxicity.[32] inhibitory effects on α-glycosidase, DNA Ismail et al. studied the phytochemicals in K. polymerase, NO production, and antioxidant and laurina Warb. stem barks for neuroprotective effects neuroprotective effects. The structural features of the in microglia cells and living brain tissue with flavonoids, such as the presence of methoxy, exposure to hydrogen peroxide (H2O2). The study hydroxy, and methylenedioxy groups, play a crucial successfully procured five flavonoids, namely, role in determining their bioactivities and their luteolin (27), (+)-catechin (39), (−)-catechin (40), position in the structure.[40] For instance, 7,4′-dihydroxy-3′-methoxyflavan (38), and 5,7,3′- kenamavoids A and B, 7,2′-dihydroxy-6,8-dimethyl- trihydroxy-4′-methoxyflavan (41).[15] In another 4′,5′-methylenedioxyflavan, kaempferol-3-methyl study, Rangkaew et al. biochanin A (37) was ether, and sulfuretin demonstrated moderate extracted from K. furfuraceae Warb. stems, which inhibitory effects on α-glycosidase possibly due to was weakly cytotoxic against the NCI-H187 cell their methylenedioxy groups and the presence of line.[33] Wang et al. isolated flavonoids 7,4′- hydroxyl in the position 2 of the A ring.[41] 2′- dihdroxy-4′-methoxyflavanol (33), (2S)-3′,4′,7- hydroxy-7-methoxy-4′,5′-methylenedioxyflavan trihydroxyflavan (34), (2S)-7,3′-dimethoxy-4′- showed remarkable scavenging activities against hydroxyflavan (35), and fisetinidol (36) from the DPPH and ABTS, which might be attributed to the leaves of the same species. The metabolites were presence of methoxy and hydroxy groups, also subjected to inhibitory assessment against nitric additionally, the 2, 3 double bond on the C-ring also oxide (NO) production in LPS-activated RAW264.7 plays a significant role.[42,43] Myristine A and D were macrophages, of which (33) and (34) were revealed reported to be the most potent DNA polymerase β to be significantly active with IC50 of 13.79 and 9.28 inhibitors, and their cytotoxicity was enhanced when µM, respectively.[38] combined with bleomycin.[43] These findings suggest Rangkaew and co-workers published another that flavonoids from Knema species possess report on the fruits of another Knema species, K. significant potential as natural agents for various glauca Warb. The study obtained a flavan from the therapeutic applications. fruit, myristinin D (32). Myristinin A (31) and 7,4′- The high number of flavonoids found and dihydroxy-3′-methoxyflavan (38) were also isolated in the Knema genus can be explained by the documented from the leaves and stems of K. glauca fact that these plants are found in the tropical regions Warb.[37] Notably, (31) and (32) were of Asia, where they are exposed to environmental cyclooxygenase enzyme inhibitors and cytotoxic to stressors such as UV radiation, pathogens, and Vero cells at IC50 values of 17.7 and 13.6 µg/mL, herbivores in their tropical habitats.[10] As a defense © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 402
25728288, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202200224 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Flavonoids and other constituents of plants… mechanism, Knema species have evolved to (figure 3) from nine species. Table 2 lists the synthesize a diverse range of secondary metabolites, isolated phenolics from the genus Knema, where K. including flavonoids, to protect themselves against elegans Merr. comprised the highest number of these stressors. Additionally, flavonoids play reported isolated phenolics (seven compounds). essential roles in plant physiology, such as Gonzalez et al. were the first to extract phenolics pigmentation, attracting pollinators, and regulating from Knema, in which l-(2,6-dihydroxyphenyl)- growth and development. The abundance of tetradecan-l-one (68), 1-(2,6-dihydroxyphenyl)-9- flavonoids in Knema species may also be due to phenylnonan-l-one (75) and (Z)-1-(2,6- selective breeding or natural selection for their dihydroxyphenyI)-tetradecan-l-one (76) were medicinal properties.[10] Many of these compounds obtained from K. austrosiamensis de Wilde. have shown pharmacological activities that make woods.[26] Zahir and co-workers isolated two them attractive candidates for use in traditional folk compounds structurally related to an antibiotic, 5- medicine. alkylresorcinol, from the leaves of K. furfuraceae Warb., which were knerachelins A (63) and B (64). 2.2. Phenolics Both compounds were active against Streptococcus aureus and Streptococcus pneumonia with a MIC Knema reportedly contains 29 phenolics (51-79) value of 8 µg/mL.[24] R O HO HO O n m n OH HO n 9 51 n = 10 ; R = H 52 m=7;n=3 HO OH 53 54 55 n = 12 72 n = 12 ; R = CO2H 62 m=7;n=5 79 n = 14 ; R = H 73 m=9;n=3 56 n = 10 74 m=9;n=5 77 m=7;n=7 78 m=7;n=5 COOH COCH3 HO HO HO HO O n n n 4 O OH OH OH 57 n = 12 58 n = 10 60 n = 12 61 59 n = 12 OH O OH O OH COCH3 HO OCH3 HO n n n R OH R R OH OH 63 R = OCH3 ; n = 4 66 R = OH ; n = 10 69 R = OH OH 64 R=H;n=4 68 R = H ; n = 12 70 R = H 71 n = 8 65 R=H;n=9 67 R = OH ; n = 9 75 R=H;n=8 OH O 6 4 R OH 76 R = H Figure 3: Chemical structures of the phenolic compounds isolated from the genus Knema The isolation of seven phenolics; colorless oil-like substance with optical activity kneglomeratanol (54), 3-(12′-phenyldodecyl)phenol [α]D-8.3°, has never been procured. All compounds (55), 3-(10′-phenyldecyl)phenol (56), 5- were cytotoxic to three human cancer cell lines, A- pentadecylresorcinol (57), 5-(10′- 549 (lung carcinoma), MCF-7 (breast carcinoma), phenyldecyl)resorcinol (58), 5-(12′- and HT-29 (colon adenocarcinoma). Furthermore, phenyldodecyl)resorcinol (59), and 2-hydroxy-6- the compound prevented the formation of crown gall (12′-phenyldodecyl)benzoic acid (60) from K. tumors on the discs of potato tubers.[27] elegans Merr. stem barks, together with some The activity-guided chromatographic isoflavonoids, were reported.[27] Compound (54), a purification of K. hookeriana Warb. methanol © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 403
25728288, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202200224 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Wan Mohd Nuzul Hakimi Wan Salleh et al. extract utilizing pine wood nematode pronounced antinematodal component (52) was Bursaphelenchus xylophilus successfully isolated novel. The compounds also exhibited a strong and characterized 3-undecylphenol (51) and 3-(8Z- antinematodal activity with a minimum effective tridecenyl)-phenol (52).[29] The study was the first to dose (MED) of 4.5 and 20 µg/cotton ball.[29] procure (51) from the species. Moreover, the Table 2: Phenolics isolated from the genus Knema No Phenolic Species Plant part 51 3-Undecylphenol K. hookeriana Bark[19] 52 3-(8Z-tridecenyl)-phenol K. hookeriana Bark[19] 53 Vanillic acid K. saxalitis Leaves[22] 54 Kneglomeratanol K. glomerata Stem bark[17] 55 3-(12'-Phenyldodecyl)phenol K. glomerata Stem bark[17] 56 3-(10'-Phenyldecyl)phenol K. glomerata Stem bark[17] 57 5-Pentadecylresorcinol K. glomerata Stem bark[17] 58 5-(10'-Phenyldecyl)resorcinol K. glomerata Stem bark[17] 59 5-(12'-Phenyldodecyl)resorcinol K. glomerata Stem bark[17] 60 2-Hydroxy-6-(12'-phenyldodecyl)benzoic acid K. glomerata Stem bark[17] K. tenuinervia Stem bark[5] 61 Kneglobularone B K. globularia Root[9] 62 3-(8Z-pentadecenyl)phenol K. tenuinervia Stem bark[5] 63 Knerachelins A K. furfuracea Leaves[14] 64 Knerachelins B K. furfuracea Leaves[14] 65 Malabaricone A K. glauca Fruit[23] 66 Dodecanoylphloroglucinol K. glauca Fruit[23] 67 1-(2,4,6-Trihydroxyphenyl)-9-phenylnonan-1-one K. glauca Fruit[23] 68 1-(2,6-Dihydroxyphenyl) tetradecan-1-one K. glauca Fruit[23] K. austrosiamensis Wood[16] 69 3-(12-Phenyldodecyl)-phenol K. globularia Root[11] 70 Undecylphenol K. globularia Root[11] 71 Kneglomeratanone A K. globularia Root[11] 72 6-Tridecylsalicylic acid K. globularia Root[11] 73 3-Pentadec-10′(Z)-enylphenol K.laurina Stem bark[21] 74 3-Heptadec-10ʹ(Z)-enylphenol K.laurina Stem bark[21] 75 1-(2,6-Dihydroxyphenyl)-9-phenylnonan-l-one K. austrosiamensis Wood[16] 76 (Z)-1-(2,6-DihydroxyphenyI)-tetradecan-l-one K. austrosiamensis Wood[16] 77 3-(Heptadec-8-enyl)phenol K. stellate Leaves[31] 78 3-(Pentadec-8-enyl)phenol K. stellate Leaves[31] 79 3-Pentadecylphenol K. stellate Leaves[31] Four acylphenols, including malabaricone A was the most active compound when evaluated for (65), dodecanoylphloroglucinol (66), 1-(2,4,6- antiviral activity against herpes simplex virus type 1, trihydroxyphenyl)-9-phenylnonan-1-one (67), and 1- documenting an IC50 value of 3.05 µg/mL. (2,6-dihydroxyphenyl) tetradecan-1-one (68), were Furthermore, a significant antimalarial property extracted from K. glauca Warb. fruits and against the Plasmodium falciparum parasite at 2.78 characterized.[23] Compounds (65), (67), and (68) µg/mL IC50 value was also recorded by (65).[33] demonstrated antituberculosis activity against The separation and purification of two alkenyl Mycobacterium tuberculosis with MIC values of 25, phenols resulted from a bioassay-guided extraction 50, and 100 µg/mL, respectively. Compound (66) of K. laurina Warb. stem bark and repeated column © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 404
25728288, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202200224 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Flavonoids and other constituents of plants… chromatography of its hexane and dichloromethane activity against herpes simplex virus type 1 is likely fractions.[31] In the study, a novel 3-pentadec-10′(Z)- due to the ability of dodecanoylphloroglucinol to enylphenol (73) and 3-heptadec-10ʹ(Z)-enylphenol disrupt the viral envelope and inhibit virus (74) were also procured. Compounds (73) and (74) replication.[43] Furthermore, the cytotoxic activity of exhibited weak acetylcholinesterase inhibitory the isolated phenolic compounds against various activity with IC50 values of 17.2 and 13.1 µg/mL, cancer cell lines is attributed to their ability to respectively. Sriphana and co-workers also studied induce cell death through various mechanisms, the bioactive compounds in Thai Knema species. In including apoptosis and cell cycle arrest. For their study, the hexane extracts of K. globularia example, kneglomeratanol, 3-(12′- Warb. roots were fractionated by silica gel column phenyldodecyl)phenol, 3-(10′-phenyldecyl)phenol, chromatography and preparative TLC to yield four 5-pentadecylresorcinol, 5-(10′-phenyldecyl)- known phenolics and other compounds of different resorcinol, 5-(12′-phenyldodecyl)resorcinol, and 2- groups, 3-(12-phenyldodecyl)-phenol (69), hydroxy-6-(12′-phenyldodecyl)benzoic acid isolated undecylphenol (70), kneglomeratanone A (71), and from K. elegans Merr. stem barks induce apoptosis 6-tridecylsalicylic acid (72). Compound (70) in A-549, MCF-7, and HT-29 cancer cell lines.[27] revealed weak cytotoxic activity against KB, MCF- The induction of apoptosis is likely due to the ability 7, and NCIH187 cell lines with IC50 values ranging of these compounds to activate caspases, which are from 28 to 48 mg/mL, while substances (69-72) key regulators of apoptosis. exhibited inactive cytotoxicity against the same cell lines. Moreover, the isolates demonstrated no 2.3. Anacardic Acids antimalarial activity against P. falciparum.[19] Vanillic acid (53), a phenol, was extracted from K. Since 2011, twelve anacardic acids (80-92) (figure saxatilis leaves. The compound is the only known 4) have been successfully isolated from the genus phenolic compound isolated from the species.[32] In Knema as listed in Table 3. Anacardic acid was another study, it was reported that the leaves of K. never procured from the plants in the genus, which stellata Merr. yielded 3-(heptadec-8-enyl)-phenol Akhtar and colleagues first extracted in 2011. Their (77), 3-(pentadec-8-enyl)-phenol (78), and 3- study documented the isolation of three anacardic pentadecylphenol (79).[45] acids; (+)-2-hydroxy-6-(10′-hydroxypentadec-8′(E)- Overall, the isolated phenolic compounds from enyl)benzoic acid (90), 2-hydroxy-6-(pentadec- various Knema Lour. species exhibit a wide range of 10ʹ(Z)-enyl)benzoic acid (91), and 2-hydroxy-6- biological activities, including cytotoxic, (10′(Z)-heptadecenyl)benzoic acid (92) from K. antimicrobial, antinematodal, antituberculosis, laurina Warb. stem barks. Among the anacardic antiviral, antimalarial, and antioxidant activities. acids, compound (90) has never been obtained. These activities are mainly attributed to the chemical Compound (92) exhibited potential AChE inhibitory structures of the phenolic compounds, which contain attributes with a 0.57 µM IC50 value.[31] Akhtar et al. various functional groups such as hydroxyl, suggested that anacardic acid might be a fresh model carboxyl, and methoxy groups. Knerachelins A and for future structural alterations to novel drugs. The B isolated from K. furfuraceae Warb. leaves are hypothesis arose from docking studies that structurally related to an antibiotic, 5- demonstrated that the long side chain of the acid alkylresorcinol, and exhibit antimicrobial activity might enable entry to enzyme active sites at a deep against Streptococcus aureus and Streptococcus level. Moreover, the acid could organize itself pneumonia. This activity is likely due to the long through p-p interactions, hydrogen bonds, and alkyl chain, which enhances the compounds' hydrophobic contacts with some critical residues lipophilicity and ability to interact with the bacterial along the intricate geometry of the active gorge.[31] cell membrane, leading to cell death. The The ethyl acetate fraction of K. hookeriana Warb. acylphenols, including malabaricone A, stem barks were studied, and three new anacardic dodecanoylphloroglucinol, 1-(2,4,6- acids were procured, namely, khookerianic acid A trihydroxyphenyl)-9-phenylnonan-1-one, and 1-(2,6- (81), khookerianic acid B (82), and khookerianic dihydroxyphenyl) tetradecan-1-one, extracted from acid C (83). Anagigantic (84), (Z)-2-hydroxy-6- K. glauca Warb. fruits exhibit various activities such (tridec-8-en-1-yl)benzoic (85), 2-hydroxy-6- as antituberculosis, antiviral, and antimalarial tridecylbenzoic (86), and (Z)-2-hydroxy-6- activities. The antituberculosis activity is attributed (pentadec-10-en-1-yl)benzoic (87) acids were also to the presence of the phloroglucinol moiety, which documented.[20] Giap et al. reported the chemical has been reported to inhibit the growth of compositions, cytotoxicity, and acetylcholinesterase Mycobacterium tuberculosis.[42] The antiviral inhibitory activities of phytochemicals from K. © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 405
25728288, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202200224 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Wan Mohd Nuzul Hakimi Wan Salleh et al. pachycarpa de Wilde. fruits. The study recorded two lines, while no cytotoxicity was detected against the anacardic acids, knepachycarpic acid A (88) and Hep3B cell line at 100 µM concentration for all knepachycarpic acid B (89). The compounds were compounds.[46] weakly active against Hela and MCF-7 cancer cell Table 3: Anacardic acids isolated from the genus Knema No Anacardic Acids Species Plant part 80 (E)-2-Hydroxy-6-(pentadec-8-en-1-yl) benzoic acid K. furfuracea Twigs and leaves[18] 81 Khookerianic acid A K. hookeriana Stem bark[10] 82 Khookerianic acid B K. hookeriana Stem bark[10] 83 Khookerianic acid C K. hookeriana Stem bark[10] 84 Anagigantic acid K. hookeriana Stem bark[10] 85 (Z)-2-Hydroxy-6-(tridec-8-en-1-yl)benzoic acid K. hookeriana Stem bark[10] 86 2-Hydroxy-6-tridecylbenzoic acid K. hookeriana Stem bark[10] 87 (Z)-2-Hydroxy-6-(pentadec-10-en-1-yl)benzoic acid K. hookeriana Stem bark[10] 88 Knepachycarpic acid A K. pachycarpa Fruit[32] 89 Knepachycarpic acid B K. pachycarpa Fruit[32] 90 (+)-2-Hydroxy-6-(10ʹ-hydroxypentadec-8ʹ(E)- K. laurina Stem bark[21] enyl)benzoic acid 91 2-Hydroxy-6-(pentadec-10ʹ(Z)-enyl)benzoic acid K. laurina Stem bark[21] 92 2-Hydroxy-6-(10ʹ(Z)-heptadecenyl)benzoic acid K. laurina Stem bark[21] COOH COOH COOH HO HO HO O m n n n O 80 m=7;n=6 81 n = 8 88 n = 12 82 m=5;n=3 84 n = 10 89 n = 10 83 m=5;n=4 86 n = 12 85 m=7;n=3 91 m=9;n=3 COOH 92 m=9;n=5 HO m n OH 90 m = 7 ; n = 4 Figure 4: Chemical structures of the anacardic acids isolated from the genus Knema Wang and colleagues extracted (E)-2-hydroxy-6- can improve cognitive function and memory. The (pentadec-8-en-1-yl) benzoic acid (80) and other observed AChE inhibitory activity of the compound important groups of compounds from K. furfuraceae (92) suggests that it may have potential as a Warb. The inhibitory properties of the compounds treatment for Alzheimer’s disease. On the other were evaluated on the nitric oxide (NO) production hand, nitric oxide (NO) is a free radical involved in in LPS-activated RAW264.7 macrophages. various physiological processes, including Nevertheless, compound (80) demonstrated no neurotransmission, immune defense, and vascular activity.[28] regulation. Overproduction of NO is associated with The mechanism of action for the observed several pathological conditions, including activities of anacardic acids is attributed to their inflammation and cancer. The observed inhibitory ability to inhibit the activity of acetylcholinesterase activity of some anacardic acids, such as compound (AChE) and nitric oxide (NO) production. AChE is (80), against NO production, suggests that they may an enzyme that catalyzes the breakdown of have potential as anti-inflammatory and anticancer acetylcholine, a neurotransmitter involved in agents. In addition to their biological activities, the transmitting nerve impulses in the brain. Inhibition long side chain of anacardic acids, such as that in of AChE increases the level of acetylcholine, which compound (90), allows them to interact with enzyme © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 406
25728288, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202200224 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Flavonoids and other constituents of plants… active sites at a deep level, suggesting that they may ketone, containing an aromatic and aliphatic group. be a promising scaffold for the development of Table 4 lists all acetophenones procured from the novel drugs. The ability of anacardic acids to form genus Knema. Six novel compounds, including three pi-pi interactions, hydrogen bonds, and hydrophobic acetophenone derivatives, were isolated from the contacts with critical residues in the active site of ethyl acetate extract of K. hookeriana Warb. stem enzymes suggests that they have a broad range of barks. The compounds were extracted and biological activities and potential therapeutic characterized for the first time, known as applications.[31] khookerianone A (93), khookerianone B (94), and khookerianone C (95). Nevertheless, three novel 2.4. Acetophenones compounds were inactive in Bcl-xL/Bak and Mcl- 1/Bid interaction modulations.[20] Acetophenone (93-101) (figure 5) is the simplest COCH3 COCH3 COCH3 HO HO HO O n m n n O OH OH 93 n = 11 94 m = 5 ; n = 3 96 n = 8 99 n = 8 95 m = 7 ; n = 3 97 n = 10 101 n = 11 COCH3 HO n OH 98 n = 8 100 n = 10 Figure 5: Chemical structures of the acetophenones isolated from the genus Knema Table 4: Acetophenone isolated from the genus Knema No Acetophenone Species Plant part 93 Khookerianone A K. hookeriana Stem bark[10] 94 Khookerianone B K. hookeriana Stem bark[10] 95 Khookerianone C K. hookeriana Stem bark[10] 96 Knepachycarpanone A K. pachycarpa Stem[12] 97 Knepachycarpanone B K. pachycarpa Stem[12] 98 Kneglomeratanones A K. glomerata Stem bark[17] 99 Kneglomeratanones B K. glomerata Stem bark[17] 100 2,4-Dihydroxy-6-(10ʹ-phenyldecyl)acetophenone K. glomerata Stem bark[17] K. tenuinervia Stem bark[30] 101 Kneglobularone A K. globularia Root[11] Two new acetophenone derivatives, significant toxicity against three human tumor cell knepachycarpanone A (96) and knepachycarpanone lines and inhibited the growth of crown gall tumors B (97) were discovered from K. pachycarpa de on potato tuber discs.[27] Compound (100) was also Wilde. stem.[22] In another study, two novel extracted from K. tenuinervia de Wilde. stem acetophenones, kneglomeratanones A (98) and B barks.[39] The isolation of a novel acetophenone, (99) and 2,4-dihydroxy-6-(10′-phenyldecyl)aceto- kneglobularone A (101), exhibited moderate phenone (100), were successfully isolated from K. cytotoxicity against the NCI-H187, KB, and Vero elegans Merr. stem barks.[27] The study utilized brine cell lines with IC50 values ranging from 8.2 to 13.0 shrimp lethality for activity-guided chromatographic mg/mL was also reported.[19] Compound (100) fractionation. All compounds exhibited moderate but contains a phenyldecyl group, which may contribute © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 407
25728288, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202200224 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Wan Mohd Nuzul Hakimi Wan Salleh et al. to its cytotoxicity by interacting with cellular metabolites comprise cardanols, lignans, cardol, membranes and disrupting their structure and sterols, sesquiterpenes, coumarin, and stilbenes function. (102-121) (figure 6). A phytochemical investigation of K. saxalitis de Wilde. leaves yielded three sterols; 2.5. Miscellaneous Constituents stigmast-4-ene-3,6-dione (112), sitoindoside (113), and 5β-hydroxysitostanol (114), one sesquiterpene; Table 5 summarises other phytochemicals clovan-2β,9α-diol (115), and one lignan; (+)- documented from various Knema species. The isolariciresinol (107).[32] K. pachycarpa de Wilde. OH HO HO HO O HO HO m n n OH n R O OH O 102 n = 12 103 m = 7 ; n = 12 104 n=8;R=H 107 105 n = 10 ; R = H 106 n = 12 ; R = H 113 n = 10 ; R = OH R3 R3 O CH3 O O R4 R4 O CH3 O O R1 R1 OH R2 R2 108 109 R1 = R2 = R3 = R4 = OCH2O 110 R1 = R2 = R3 = R4 = OCH2O H3CO CH3 HO CH3 R3 H3CO R1 n O O OCH3 R4 R2 OH OH O 111 118 112 R1 = R2 = R3 = R4 = OCH2O O O O 13 O HO OH OH O HO O OH 114 115 116 R2 OH HO OCH3 R1 OH HO OH H3CO OCH3 121 117 119 R1 = R2 = OH 120 R1 = OCH3 ; R2 = OH Figure 6: Chemical structures of the miscellaneous compounds isolated from the genus Knema © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 408
25728288, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202200224 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Flavonoids and other constituents of plants… Table 5: Miscellaneous compounds isolated from the genus Knema No Miscellaneous Group Species Plant part 102 3-Tridecylphenol Cardanol K. hookeriana Stem bark[10] 103 (Z)-3-(Tridec-8-en-1-yl)phenol Cardanol K. hookeriana Stem bark[10] 104 Knepachycarpanol C Cardanol K. pachycarpa Stem[32] 105 Knepachycarpanol A Cardanol K. pachycarpa Fruit[32] 106 Knepachycarpanol B Cardanol K. pachycarpa Fruit[32] 107 (+)-Isolariciresinol Lignan K. saxalitis Leaves[22] 108 Attenuol Lignan K. attenuata Bark[13] 109 Sesamin Lignan K. glauca Fruit[23] 110 Asarinin Lignan K. glauca Fruit[23] 111 (+)-trans-1,2-Dihydrodehydroguaiaretic Lignan K. furfuracea leaves[28] acid 112 Fragransin A Lignan K. furfuracea leaves[28] 113 Knepachycarpasinol Cardol K. pachycarpa Fruit[32] 114 Stigmast-4-ene-3,6-dione Sterol K. saxalitis Leaves[22] 115 Sitoindoside I Sterol K. saxalitis Leaves[22] 116 5β-Hydroxysitostanol Sterol K. saxalitis Leaves[22] 117 Clovan-2β,9α-diol Sesquiterpene K. saxalitis Leaves[22] 118 8-Hydroxy-6-methoxy-3- Coumarin K. tenuinervia Stem bark[30] pentylisocoumarin 119 3,4′-Dimethoxy-5-hydroxystilbene Stilbene K. austrosiamensis Wood[16] 120 3,5-Dihydroxy-4′-methoxystilbene Stilbene K. austrosiamensis Wood[16] 121 1-(2-Methoxy-4-hydroxyphenyl)-3-(3- Stilbene K. austrosiamensis Wood[16] hydroxy-4-methoxyphenyl)-propane fruits reportedly contain two novel cardanols, pentylisocoumarin (116), from K. tenuinervia de knepachycarpanols A (105) and B (106), and a new Wilde. stem barks.[49] cardol, knepachycarpasinol.[48] Compounds (105) and (111) were the most active in 3. CONCLUSION acetylcholinesterase, recording IC50 values of 2.6 and 2.4 µM, respectively. Conversely, compounds In conclusion, this review comprehensively (106) and (111) documented moderate cytotoxicity overviews the various flavonoids and other chemical towards Hela and MCF-7 cancer cell lines at IC50 components in the genus Knema and their associated values of 31.3-41.3 µM.[48] Another study isolated a pharmacological properties. The research indicates novel cardanol, knepachycarpanol C (104), from K. that the plants in this genus are promising candidates pachycarpa de Wilde. stems.[22] for developing new drugs, with a range of bioactive Three stilbenes; 3,4′-dimethoxy-5- flavonoids demonstrating significant cytotoxicity hydroxystilbene (119), 3,5-dihydroxy-4′- and antitumor activity. The potential for further methoxystilbene (120), and 1-(2-methoxy-4- exploration of this genus is highlighted by the fact hydroxyphenyl)-3-(3-hydroxy-4-methoxyphenyl)- that there are over 60 species, yet only 14 have been propane (121) were successfully isolated from K. studied for their phytochemical composition and austrosiamensis de Wilde. woods. Moreover, three pharmacological activities. As such, there is a wealth lignans were procured, of which sesamin (109) and of untapped potential in Knema plants for asarinin (110) were obtained from K. glauca Warb. discovering novel bioactive compounds with fruits [38] and attenuol (108) from K. attenuate Warb. potential therapeutic applications. Further research is barks.[23] Two cardanols from K. hookeriana Warb. required to fully characterize the compounds in stem barks, 3-tridecylphenol (102), and (Z)-3- Knema plants, their mechanisms of action, and their (tridec-8-en-1-yl)phenol (103), were reported by potential applications in drug development. Despite Geny and his coworkers[20] while Pinto et al. the current limitations, the future perspectives of the extracted a coumarin, 8-hydroxy-6-methoxy-3- genus Knema are exciting and may lead to the © 2023 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 409
25728288, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/vjch.202200224 by Readcube (Labtiva Inc.), Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Vietnam Journal of Chemistry Wan Mohd Nuzul Hakimi Wan Salleh et al. development of novel therapies and interventions for 14. J. Sinclair. The genus Knema (Myristicaceae) in various health conditions. Malaysia and outside Malaysia, Singapore: Garden Bulletin, 1961. REFERENCES 15. H. R. Supriya, G. B. Sreekanth. Phytopharmacological review of Knema attenuata 1. M. Mohammadhosseini, A. Venditti, C. Frezza, M. (Hook F. and Thomson) Warb., Int. J. Curr. Pharm. Serafini, A. Bianco, B. Mahdavi. The genus Res., 2021, 1, 1-3. Haplophyllum Juss.: phytochemistry and 16. C. Geny, G. Riviere, J. Bignon, N. 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