Synthesis and cytotoxicity of natural (-)-quinocarcin and its related compounds

Abstract: The title synthesis was accomplished by featuring highly diastereo-selective reduction of the 1,3-disubstituted isoquinoline 10 to control stereochemistries at the C5 and C11a positions in la simultaneously in a single step. l n vitro cytotoxicity assay of the synthesized quinocarcin congeners including their enantiomers disclosed novel aspects of saucture-activity relationships and explored the unnatural 10-decarboxyquinocarcin derivatives lb, 3b, and 4b which are more highly cytotoxic than the corresponding natural 10-carboxy compounds la, 3a, and 4a. (-)-Quinocarcin [(-)-la] isolated from the culture broth of Streptomyces melunovinuceus in 1983, exhibits prominent antitumor activity against various types of mammalian solid tumors (ref.1 and 2). Quinocarcinol (2a), the pharmacologically inactive dihydroderivative of la, was also isolated from the same culture broth (ref.1 and 2). While la is fairly unstable, cyanation of la with sodium cyanide can produce the more stable hydrogen cyanide adduct, DX-52-1 (3a), which still retains significant antitumor activity (ref. 2). It is also reported that treatment of 3a with silver nitrate cleanly regenerates la (ref. 2). The stereostructure of l a except its absolute configuration was revealed by a combination of X-ra