Novel Glu-based pyrazolo[3,4-d]pyrimidine analogues: design, synthesis and biological evaluation as DHFR and TS dual inhibitors

Abstract

A novel series of multifunctional pyrazolo[3,4-d]pyrimidine-based glutamate analogs (6a–l and 7a,b) have been designed and synthesized as antifolate anticancer agents. Among the tested compounds, 6i exhibited the most potent anti-proliferative activity towards NSCLC, CNS, Ovarian, Prostate, Colon, Melanoma, Breast, and Renal cancers with good to weak cytostatic activity and non-lethal actions. 6i demonstrated higher selectivity for cancer than normal cells. 6i could significantly increase the accumulation of S-phase cells during the cell cycle distribution of cancer cells with high potency in the induction of apoptosis. The results unveiled that 6i probably acts through dual inhibition of DHFR and TS enzymes (IC₅₀ = 2.41 and 8.88 µM, correspondingly). Docking studies of 6i displayed that N1-p-bromophenyl and C3-Methyl groups participate in substantial hydrophobic interactions. The drug-likeness features inferred that 6i met the acceptance criteria of Pfizer. Taking together, 6i could be a promising prototype for further optimization as an effective anticancer drug.

Keywords:

• DHFR
• TS
• pyrazolo[34-d]pyrimidine
• NCI
• Glu

Acknowledgements

The authors would like to express their gratitude and thanks to the Deanship of Scientific Research at Najran University for Funding this work under the National Research Priority program grant code (NU/DRP/MRC/12/1). The authors extend their appreciation to OpenEye Scientific Software for providing the academic licence.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This research was funded by Deanship of Scientific Research at Najran University, grant number NU/DRP/MRC/12/1”.