The synthesis of 11-substituted 6-amino-11,12-dihydrobenzo[c]phenanthridines and 11-substituted 6-aminobenzo[c]phenanthridines through an efficient method is described. The antiproliferative activity of selected compounds against a wide panel of tumor cell lines was tested in the in vitro anticancer screening and the in vivo hollow fiber assay of the National Cancer Institute. Several compounds turned out to exhibit considerable cytotoxicity for tumor cells. For the study of structure-activity relationships different substituents were introduced in the 11-position. Compounds with methoxyphenyl substituents tended to show the highest potency. Several compounds exhibited noteworthy antitumor activity with GI(50) values across all cell lines <1 microM. 6-Amino-11-(3,4,5-trimethoxyphenyl)benzo[c]phenanthridine perchlorate was the most potent agent in the NCI's in vivo hollow fiber assay. Most of the tested compounds showed a remarkable selectivity for leukemia, breast cancer, and prostate cancer.
Starting from 4‐chlorocoumarin‐3‐carbaldehyde (1) and Wittig phosphoranes 2a‐d the title compounds 6a‐c have been synthesized via a four‐step sequence. The intermediate 4‐alkylamino‐3‐vinylcoumarins 5a‐k have been prepared by the reaction of 4‐chloro‐3‐vinylcoumarins 3a‐d with primary amines 4a‐h. The coumarin derivatives 5 (except 5k) underwent an unusual pyridine ring closure under Vilsmeier conditions to form the benzopyrano[4,3‐b]pyridines 6. When the aminoaldehydes 7 were treated with the Wittig reagent 2b the fused N‐alkyl‐2(1H)‐pyridinones 8 have been obtained as expected.
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