Antineoplastic agents. 600. From the South Pacific Ocean to the silstatins.

ABSTRACT

The recent advances in the development of antibody and other drug conjugates for targeted cancer treatment have further increased the need for powerful cancer cell growth inhibitors. Toward that objective we have extended our earlier discovery of the remarkable anticancer bacillistatins 1 and 2 from Bacillus silvestris to SAR and other structural modifications such as availability of a free hydroxy group for antibody-drug conjugate (ADC) and other prodrug linkage. That direction has resulted in seven structural modifications designated silstatins 1-8 (7a, 8a, 8b, 14a, 15a, 15b, 18a, and 18b), where the exceptional cancer cell growth inhibition of some of them are in the range GI50 10(-3)-10(-4) µM/mL. Silstatin 7 (18a) was converted to a glucuronic conjugate (28) that displayed an impressive reduction in toxicity during transport.