Novel Approaches in the Synthesis of Batracylin and Its Analogs: Rebirth of an Old Player?
Abstract:Batracylin (8-aminoisoindol[1,2-b]-quinasolin-12(10H)-one, BAT), a heterocyclic amine, was isolated in 1978 (NCI, Bethesda, USA) in the course of search for the new anticancer drugs. It showed high in vitro and in vivo anticancer activities against murine leukemia P338 and colon adenocarcinoma 38. Mechanism of action of BAT is still not completely clear. It was reported, that BAT is a topoisomerase II inhibitor and induces unscheduled DNA synthesis (UDS) in non-proliferating cells. Low solubility of BAT in water, high toxicity and necessity of high drug dosing are major limitations of its use as a chemotherapeutic drug. As a result, new BAT analogs were synthesized to improve its pharmacological properties. The modifications of BAT chemical structure include various substituents introduced to isoindoloquinazoline moiety (Cl, Br, NO2, CH2, NH2, Me, CO2Me, OMe). It has been shown that the desamino derivative and the 8-aza analog of BAT retained the ability to inhibit topoisomerase II but did not induce unscheduled DNA synthesis. While less active than BAT, these analogs were cytotoxic toward 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. Batracylin was acylated with aminoacids, dipeptides, tripeptides to increase its solubility in water. Other modifications include introduction of nitrogen atom to ring A or D, extension of polycyclic ring 4, reduction of ring B from six- to five-membered one, and obtaining of benzimidazole, indole or derivatives containing a fucose ring. A series of novel BAT analogs bearing sugar residues and thiocarbonyl aminoacids, which provided better solubility in water and high cytostatic activity have been designed. Also, new azabatracylines, where aniline ring was replaced by pyridine or other substituted quinazolines, have been obtained. This paper reviews the most important approaches in batracylin synthesis and its analogs and presents structure-reactivity relationships for these compounds.
Document Type: Research Article
Publication date: September 1, 2012
More about this publication?
- Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.