- 期刊
Intercalating and Antitumour Activity of 4-Oxopyrimido[4',5':4,5]Thieno(2,3-b)quinoline-4(3H)-one
並列摘要
AIM: The study was aimed to analyze the physicochemical properties of the 4-Oxopyrimido[4',5':4,5]thieno(2,3-b)quinoline-4(3H)-one (Oxo-PTQ) with DNA in an attempt to understand its biological activity. This research offers a new intercalation functional group to DNA targeted drug design. METHODS: Biophysical studies such as UV-visible absorbance, fluorescence, hydrodynamic methods, and circular dichroism were performed to study the interaction of Oxo-PTQ with DNA. Cytotoxicty was evaluated on K-562, HL-60, Neuro 2a, and B16F10 cancer cell lines. Antitumour efficacy was evaluated on Balb/c mice carrying B16F10 murine melanoma. RESULTS: The association constant values of 2.3×10^4 M^(-1) and 2.4×10^4 M^(-1) were obtained for UV and fluorescence absorbance, respectively. Viscosity experiments with sonicated rod-like DNA fragments produced a calculated increase in length of 2.4 Å per bound Oxo-PTQ molecule. The binding of Oxo-PTQ protected DNA melting by 4.5℃. The circular dichroism spectra indicated that stacking of Oxo-PTQ with DNA induced strong helicity in the usually disordered structure of this double strand. The IC50 values for K-562, HL-60, Neuro 2a, and B16F10 cancer cells were in the range of 1.58-7.13μM. The anticancer efficacy against B16F10 melanoma has provided evidence of major anticancer activity for Oxo-PTQ. Single or multiple intraperitonial doses showed higher level of activity against the subcutaneous grafted B16F10 melanoma with a significant increase in life span. CONCLUSION: The results suggested that the compounds containing pyrimido-thienoquinoline system particularly 4-oxo derivatives might be potentially useful as antitumour agents. We conclude that the correlation of physicochemical properties of the new series of pyrimidothienoquinolines with their pharmacological properties may help in understanding the mechanism of pyrimidothienoquinoline series of compounds.