OSW saponins: facile synthesis toward a new type of structures with potent antitumor activities.
[reaction: see text] OSW saponins, featuring a 16beta,17alpha-dihydroxycholest-22-one aglycon and an acylated beta-D-xylopyranosyl-(1-->3)-alpha-L-arabinopyranosyl residue attached to the 16-hydroxyl group, have recently been discovered from a group of lily plants, which show potent antitumor activities with a novel mechanism of action. This paper describes an aldol approach to the stereoselective construction of the 16alpha,17alpha-dihydroxycholest-22-one structure from 16alpha-hydroxy-5-androsten-17-ones and propionates. Elaboration of the aldol adducts toward OSW-1, involving installation of the isoamyl ketone side chain, inversion of the 16-hydroxyl configuration, and selective protection of the C22-oxy function, has been explored and accomplished. In particular, the present route was found convenient for the synthesis of OSW saponin analogues with a C22-ester side chain. Thus, the 23-oxa-analogue of OSW-1 (40) was prepared starting from the industrial dehydroisoandrosterone (1) in a linear eight-step sequence and in 26% overall yield. Analogues with a variety of modified side chains were prepared, via aldol condensation with propionates of varying length, thiopropionate, and acetate (for preparation of 68-75) or via aminolysis of the 22,16-lactone 26 (for preparation of the 23-N-analogues). Cross metathesis (CM) reaction was also found feasible for modification at the final stage from C22-allyl ester 70. Valuable structure-activity relationships (SAR), together with the practical synthetic approach, have thus been provided to set a new stage for further studies on this new type of antitumor structures.
Shi
Bingfeng
B
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China.
Tang
Pingping
P
Hu
Xiaoyi
X
Liu
Jun O
JO
Yu
Biao
B
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002783:Cholestenones / Q000138:chemical synthesis* / Q000494:pharmacology; D003687:Dehydroepiandrosterone / Q000737:chemistry; D006801:Humans; D012503:Saponins / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D002783:Cholestenones; D012503:Saponins; C106408:OSW 1; D003687:Dehydroepiandrosterone