New Benzochromeno[2,3-d]Pyrimidines and Benzochromenotriazolo[1,5-c]Pyrimidines as Potential Inhibitors of Topoisomerase II

Abstract

A group of novel benzochromenopyrimidine and benzochromenotriazolopyrimidine derivatives was designed and synthesized by a series of distinct reactions, beginning with the ethyl formimidate derivative 2, and evaluated as selective inhibitors of Topoisomerase II. Hydrazinolysis of compound 2 yielded the corresponding amino–imino 7, which in turn was exploited to produce the target benzochromenotriazolopyrimidine derivatives. The chemical structures of target derivatives were assured by different elemental and spectral analyses. The antineoplastic activity of the new benzochromene derivatives against human liver (HepG2), breast (MCF7), and colon (HCT-29) cancer cells was investigated and compared to doxorubicin. Derivatives 3, 8, 11, 12, and 13 had significant (<10 µM) antiproliferative activities. With the exception of derivative 13, the other efficient anticancer agents were selective and did not affect the growth of the normal fibroblasts (WI-38). Derivatives 8, 11, and 12 elevated the expression of p53 and caspase 3, threefold–fivefold. Derivative 3 induced the expression of caspase 3 without affecting that of p53. Derivative 11 was unique in inhibiting the expression of cdk1 by approximately 60%. All derivatives (3, 8, 11, and 12) reduced the expression of topo II by 46–56%. All these derivatives induced apoptosis as indicated by the elevation (∼fourfold–fivefold) in the activity of the cleaved active caspase 3. Derivatives 8, 11, and 12 reduced the concentration of topoisomerase II protein by approximately 50%. The antiproliferative activity of the new benzochromene derivatives is partially caused by their ability to downregulate the topoisomerase II and induce apoptosis.