ABSTRACT
A series of 6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]chromeno[6,5-g][1,8]naphthyridin-7-one (4), 13-aza derivatives of benzo[b]acronycine, the isomeric 5-methoxy-2,2,13-trimethyl-2,13-dihydro-6H-benzo[b]chromeno[7,6-g][1,8]naphthyridin-6-one (5), and related cis-diols mono- and diesters were designed and synthesized. Their in vitro and in vivo biological activities were evaluated. As previously observed in the acronycine series, esters were the most potent derivatives exhibiting submicromolar activities; among them monoesters are particularly active. Racemic diacetate 21 showed a strong activity against KB-3-1 cell lines and was selected for in vivo evaluation and proved to be active, inhibiting tumor growth by more than 80%. After separation of the two enantiomers, compounds 21a and 21b were also evaluated against C38 colon adenocarcinoma; their activities were found to be significantly different.
Subject(s)
Acronine/chemistry , Adenocarcinoma/drug therapy , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Carcinoma, Squamous Cell/drug therapy , Cell Proliferation/drug effects , Colonic Neoplasms/drug therapy , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/pharmacology , Naphthyridines/chemical synthesis , Naphthyridines/pharmacology , Adenocarcinoma/pathology , Animals , Carcinoma, Squamous Cell/pathology , Colonic Neoplasms/pathology , Drug Design , Drug Screening Assays, Antitumor , Electrophoretic Mobility Shift Assay , Humans , Inhibitory Concentration 50 , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Monocinnamoyl esters at position 2 of (+/-)-cis-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one and their acetyl derivatives at position 1 were prepared as stabilized analogues of the anticancer alkylating agent S23906-1. Monocinnamoyl esters at position 2 were slower DNA alkylators than the reference 2-monoacetate. Mixed esters bearing an acetyl ester group at position 1 and a cinnamoyl ester group at position 2 alkylated DNA slower than S23906-1. A strong correlation was observed between cytotoxicity and DNA alkylation kinetics, with slower alkylators displaying more potent antiproliferative activities. The most cytotoxic compounds proved to be significantly active in vivo against murine C-38 adenocarcinoma implanted in mice, but less potent than S23906-1.
