Synthesis of bicyclic ketones in prostaglandins and their antimitotic activity.
The synthesis of a second ring in the prostaglandin structure, located at positions C-11 and C-13, has been accomplished starting from prostaglandin A2. Also an efficient enantioselectivity was obtained through the conjugate addition of carbanions at position C-11, together with the stereospecificity of a Claisen rearrangement at position C-13. Evaluation of the inhibitory effects on the proliferation of the K-562 cell line, in vitro, is presented. A structure-activity relationship indicated that alterations of the functional groups incorporated in the second ring of the prostaglandin structure affected their hydrophobicity. The antimitotic activity for prostanoids 7b, 7c and 7e have shown substantial improvements in their activities according to their ID50 values (12.5, 9.0 and 1.12 micrograms/ml), respectively). Attention is called to the importance of derivative 7a in terms of its high potency, determined by its ID50 values (0.35 micrograms/ml).
Domínguez
J N
JN
Organic Synthesis Laboratory, Faculty of Pharmacy, Central University of Venezuela, Caracas.
Zapata
A J
AJ
Lobo
G M
GM
Blanca
I
I
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D011453:Prostaglandins / Q000138:chemical synthesis* / Q000494:pharmacology; D011465:Prostaglandins, Synthetic / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011453:Prostaglandins; D011465:Prostaglandins, Synthetic