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Here, we describe further cytotoxic studies and reverse pharmacophore mapping (pharmacophore profiling) for bis-triazoles MS44-53, which were designed and synthesized previously to stabilize the G-quadruplex nucleic acids capable of being formed at the telomeric region and promoter sequences of genes involved in cellular proliferation and oncogenes. Pharmacophore-based activity profiling screen demonstrated some biological targets that MS44-53 may modulate their biological response, and thus can be considered as potential drugs to treat different kinds of diseases, such as carcinoma, diabetes type II, bacterial infection and cardiovascular diseases. Potent cell growth inhibitory properties were shown by ligands MS47 and MS49 against human melanoma MDA-MB-435, colon cancer HCT-116 and COLO 205, and pancreatic cancer MIA PaCa-2 cell lines, as evidenced by MTT assay. Both ligands were more potent against cancer cells than in skin normal CCD-1064Sk fibroblasts.

Aim:

The aim of this study is to identify the molecular target and mechanism of action of our promising anticancer bis-triazoles MS44-53, focusing specifically on the G-quadruplex stabilizers MS47 and MS49.

Background:

In molecular biology, G-quadruplexes (also known as G4-DNA), one of the higher-order structures of polynucleotides, are four stranded structures formed by nucleic acid sequences which are rich in guanine. They are formed mainly at the single-stranded G-overhang of telomeric DNA and within promoter sequences of genes involved in cellular proliferation and oncogenes such as c-myc, c-kit, and Hsp90. Stabilization of DNA G-quadruplexes is …