Helvetica Chimica Acta (2019)
Update date:2022-07-30
Topics:
Kuzniewski, Christian N.
Glauser, Simon
Gaugaz, Fabienne Z.
Schiess, Raphael
Rodríguez-Salarichs, Javier
Vetterli, Stefan
Horlacher, Oliver P.
Gertsch, Jürg
Redondo-Horcajo, Mariano
Canales, Angeles
Jiménez-Barbero, Jesús
Díaz, José Fernando
Altmann, Karl-Heinz
A series of new 3-deoxy-C(12),C(13)-trans-cyclopropyl-epothilones have been prepared, bearing benzothiazole, quinoline, thiazol-5-ylvinyl, or isoxazol-3-ylvinyl side chains. For analogs with fused aromatic side chains, macrocyclic ring-closure was based on ring-closing olefin metathesis (RCM) of a precursor incorporating the fully elaborated heavy atom framework of the target structure (including the side chain moiety), while side chain attachment for the thiazole and isoxazole-containing 16-desmethyl analogs was performed only after establishment of the macrolactone core. Two approaches were elaborated for a macrocyclic aldehyde as the common precursor for the latter analogs that involved ring-closure either by RCM or by macrolactonization. Benzothiazole- and quinoline-based analogs were found to be highly potent antiproliferative agents; the two analogs with a thiazol-5-ylvinyl or an isoxazol-3-ylvinyl side chain likewise showed good antiproliferative activity but were significantly less potent than the parent epothilone A. Surprisingly, the desaturation of the C(10)?C(11) bond in these analogs was associated with a virtually complete loss in antiproliferative activity, which likely reflects a requirement for a ca. 60 ° C(10)?C(11) torsion angle in the tubulin-bound conformation of 12,13-trans-epothilones.
View More
Taimai Sanluck Pharmaceutical Co.,Ltd
Contact:86-592-7662921
Address:8D,No.186,Huarong Road,Huli,Xiamen,China
Suzhou Sinosun Imp.&Exp. Corporation
website:http://www.szsinosun.com
Contact:+86-512-63488895,63488616
Address:No.758 East Jiangling Road Wujiang Economic & Technological Developmenty Zone Jiangsu China
Chongqing Rong＆Quan Pharmaceutical Technology Co. , Ltd.
Contact:86-023-65268721
Address:No. 7, Manshanhong Village, Pingdingshan, Shapingba District, Chongqing Province, China
Jiangsu Wanlong Chemical Co., Ltd.
website:http://www.wanlongchem.com
Contact:+86-511-86810993 0086-511-8681 0888;
Address:Quanzhou Town, Danyang City, Jiangsu
Chemsky（shanghai）International Co.,Ltd.
Contact:0
Address:0
Doi:10.1021/ja5100367
(2014)Doi:10.1016/S0960-894X(01)00816-2
(2002)Doi:10.1016/S0960-894X(99)00519-3
(1999)Doi:10.1007/BF00906493
()Doi:10.1016/S0040-4039(00)00180-5
(2000)Doi:10.1007/BF00959671
(1991)
