A novel series of pyrazoloij3,4-d]pyrimidine derivatives were designed, synthesized and evaluated for their antiproliferative activity. Among the five compounds selected by NCI, compound 11a showed a distinctive pattern of selectivity on cell line panels and was further screened for a 5-log dose range, where it showed potent antiproliferative activity with median growth inhibition (GI 50 ) equal to 1.71 μM against the CNS cancer SNB-75 cell line. The tested derivative showed remarkably the highest cell growth inhibition against non-small cell lung cancer HOP-62, CNS cancer SNB-75, breast cancer HS578T, and melanoma MALME-3M cell lines. Flow cytometric analysis revealed that compound 11a could significantly induce apoptosis in A549 cells in vitro at low micromolar concentrations. Further investigation showed that compound 11a induced significant cell cycle arrest at G0/G1 phase partly due to its ability to downregulate cyclin D1 and upregulate p27 kip1 levels.Med. Chem. Commun. This journal is

No abstract

Cancer is a genetic disease characterized by two features: unregulated cell growth and tissue invasion (metastasis). It can be viewed as the result of a succession of genetic changes during which a normal cell is transformed into a malignant one. Evasion of cell death, apoptosis, is one of the essential changes in a cell that cause this malignant transformation. Hence, reduced apoptosis or its resistance plays a vital role in carcinogenesis. The Bcl-2 family of proteins regulates the mitochondrial apoptotic pathway. Disease states arise upon deregulation of the Bcl-2 family of proteins, where cell death is either promoted or evaded; one of the most common tactic cancer cells utilize to promote survival is anti-apoptotic protein overexpression. Specifically, Bcl-2 overexpression has been shown to be a major chemoresistance factor in a number of human cancers, and for this reason, Bcl-2 targeting is a pharmacologic priority in the quest to reactivate cell death for therapeutic benefit in cancer.

No abstract