Synthesis and Pharmacological Evaluation of Isoindolo[1,2-b]quinazolinone and Isoindolo[2,1-a]benzimidazole Derivatives Related to the Antitumor Agent Batracylin

• Published in: Journal of medicinal chemistry Vol. 37; no. 20; pp. 3434 - 3439
• Main Authors: Meegalla, Sanath K, Stevens, Gregory J, McQueen, Charlene A, Chen, Allan Y, Yu, Chiang, Liu, Leroy F, Barrows, Louis R, LaVoie, Edmond J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.09.1994; Amer Chemical Soc
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Chemistry; Chemistry, Medicinal; DNA - biosynthesis; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Humans; Indoles - chemical synthesis; Indoles - pharmacology; Indoles - therapeutic use; Isoindoles; Leukemia - drug therapy; Life Sciences & Biomedicine; Liver - drug effects; Liver - metabolism; Organic chemistry; Pharmacology & Pharmacy; Preparations and properties; Pyridones - chemical synthesis; Pyridones - pharmacology; Pyridones - therapeutic use; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Quinazolines - therapeutic use; Quinazolines - toxicity; Rats; Science & Technology; Topoisomerase II Inhibitors; Tumor Cells, Cultured; SURVIVAL; RAPID COLORIMETRIC ASSAY; RAT; DNA TOPOISOMERASE-II; ANALOGS; GROWTH; N-ACETYLATION; Antineoplastic agent; Amidine; Angular nitrogen heterocycle; Lactam; Established cell line; Enzyme inhibitor; Aromatic compound; Tetracyclic compound; In vitro; Biological activity; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00046a028

The synthesis and pharmacological activity of isoindolo[1,2-b]quinazolin-12(10H)-ones and isoindolo[2,1-a]benzimidazoles related to batracylin are described. The acute toxicity of batracyclin has been associated with the formation of its N-acetyl metabolite which is a potent inducer of unscheduled DNA synthesis in rat hepatocytes. The desamino derivative and the 8-aza analog of batracylin retained the ability to inhibit topoisomerase II but did not induce unscheduled DNA synthesis. While less active than batracylin, these analogs were cytotoxic to CCRF CEM leukemia cells. The isoindolo[2,1-a]benzimidazole derivatives were inactive as topoisomerase II inhibitors and, in general, failed to exhibit comparable antitumor activity or to induce unscheduled DNA synthesis.