Tổng hợp, xác định cấu trúc và thử hoạt tính chống ung thư dẫn xuất mới của Vinorelbin

Hoi nghi Khoa hqc ky niem 35 ndm Vien Khoa hqc vd Cong nghe Viet Nam - Hd NqilO 2010<br /> <br /> <br /> TONG HOP, XAC DINH CAU TRUC VA THlT HOAT TINH CHONG<br /> UNG THlT DAN XUAT M 6 I CUA VINORELBIN<br /> Ngo Quoc Anh'. Fanny Roussi^, Francoise Gueritte^, Nguyen Van Tuyen'<br /> 1. Vien Hda Hoc - Vien Khoa Hoc & Cdng Nghe Viet Nam<br /> 2. Institut de Chimie des Substances Naturelles - CNRS Gif-sur-Yvette, France<br /> E-mail : ngoquocanb74m(^yahoo.com<br /> Tom tat:<br /> Mdl ddn xudt m&i cd cdu «gramln» m& dugc tdng hgp di tir mudi ammoni bgc<br /> bdn cua vinorelbin. Cdu true ciia nd dd dugc xdc dinh dua vdo cdc phuong phdp<br /> phd vd so sdnh v&i cdc cdu true tuong tu dd biet. Ddn xudt dd thi hiin hoat tinh<br /> tot ddi v&i ddng te bdo ung thu KB ciing nhu hogt tinh uc chi ddi v&i qud trinh<br /> tdng hgp microtubule.<br /> Abstract:<br /> A new "gramlne " opened analogue was synthesized from an ammonium salt of<br /> vinorelblne. Its structure was elucidated by NMR, MS and compared with the<br /> known similar analogues. This analogue exhibits a good cytotoxicity on the KB<br /> cell line as well as a good inhibiting activity toward the polymerisation of<br /> lubuline.<br /> l.Mudau<br /> Vinblastin va vincristin, duge phan lap tir cay Dira Can vao cudi nhirng nam 50, hien<br /> nay van dugc sir dung rdng rai trong lam sang nhu nhirng hoa tri lieu ung thu. Chung lie che<br /> sir tdng hgp va cac chirc nang ciia microtubule, dan den lam ngung sir phan bao ciia cac te bao<br /> sdng. Nghien cuu tdng hgp va ban tdng hgp cac dan xuat ciia chiing da dugc thuc hien tir<br /> lau,[l] tap trung vao viec tao ra cac tbay ddi cau true tren "phan bae" cleavamin, [2] hoae tren<br /> "phan nam" vindolin [3] ciia cac ancaloit Dira Can. Mot trong sd dan xuat dd, vinorelbin 1<br /> (Navelbine®) dugc ban tdng hgp tir anhydrovinblastin, da the hien boat tinh chdng ung thu<br /> manh va sau dd dugc hang Pierre Fabre thuang mai boa thanh cdng nhu mot che pham chdng<br /> ung thu.<br /> <br /> •• cleavamin<br /> <br /> <br /> <br /> <br /> V vindolin<br /> HiC-' OCOCH3<br /> CHT HO I cut I H l'"'C00CH3<br /> CH3 OH<br /> <br /> <br /> Hinh 1. Cac ancaloit Dira Can<br /> Cac nghien ciiu tuong quan cau tnic - boat tinh trudc day dua ra gia thuyet rang trong<br /> qua trinh tuong tac va gan ket Ien tubulin, cau "gramin" trong cau tnic ciia vinorelbin cd the<br /> bj tdn cdng bdi mot tac nhan nucleophile dan din hieu lire boat tinh khae nhau tren invitro va<br /> invivo khi so vdi vinblastin. Tir vinorelbin, mot so dan xudt "gramin" md 2 da dugc tdng hgp<br /> dl kilm chimg gia thuyet tren tuy nhien cho din nay ehua dan xudt nao thi hien hoat tinh<br /> dang chu y tren doe tinh te bao cung nhu kha nang irc cbl tdng hgp microtubule [4] (hinh 1).<br /> Trong bai bai bao nay, chiing tdi thdng bao kit qua tdng hgp mdt dan xudt "gramin" md mdi<br /> va boat tinh chdng ung thu eiia nd.<br /> <br /> 199<br /> Tiiu ban: cdc chdt co hogi linh sinh hqc ISBN: 978-604-913-012-0<br /> <br /> <br /> 2. Ket qua nghien cihi va thao luan<br /> Chung tdi da thuc hien phan iing tao dan xuat cau "gramin" md tren mudi ammoni bae<br /> bon vinorelbin methylester 3 vdi tac nhan nucleophile lithi dimethylamid vdi hy vong thu dugc<br /> dan xudt kilu "gramin" md 4. Phan iing dien ra hoan toan va thu dugc mot san pham mdi d<br /> dang mot ddng phan lap thi duy nhdt. Phd khdi san pham do d cbl do (EST) khdng cd pic ion<br /> phan tir ciia anion triflat (TfO") chimg to san phdm thu dugc la mdt phan tir trung tinh. Tuy<br /> nhien, pic phan tir cua san phdm do d chi do (ESf) (M+H*) lai cd sd khdi bdng vdi pic cation<br /> phan tu ciia mudi ammoni bae bdn ban dau (M"").<br /> <br /> <br /> TfO ,COOMe MesNLI<br /> <br /> MeONa<br /> <br /> H3CO2C H3CO2C<br /> H3CO2C<br /> Vindolin Vindolin Vindolin<br /> <br /> 1 3 4 R = Me2N-<br /> 5 R = Meb-<br /> <br /> Sudol<br /> Can Cli vao kit qua phd khdi, thi khdng thu dugc san pham cudi kieu "gramin" md du<br /> kien. Cd hai gia thuyet ve ket qua phan iing dugc dat ra (so dd 2):<br /> - Phan ling tao ra san pham "gramin" md 4 va trong dieu kien ion hda ESI, nhdm dimethylamin<br /> de hi ion hda ban ca. Nhung cation 6 khdng ben, de dang bi phan manh de tao cation ben viing 7<br /> cd sd khdi bang vdi sd khdi ciia cation (M^) mudi ammoni bae bdn 3.<br /> - Phan ling tao ra san pham chuyen vi 9. Theo dd, ban dau LiNMe2 tan cdng cau gramin de<br /> tao dan xuat tmng gian "gramin" md 4. Sau dd LiNMe2 tiep tuc loai di H2r