108714-19-8Relevant articles and documents
Applying the designed multiple ligands approach to inhibit dihydrofolate reductase and thioredoxin reductase for anti-proliferative activity
Ng, Hui-Li,Chen, Shangying,Chew, Eng-Hui,Chui, Wai-Keung
, p. 63 - 74 (2016)
The development of multi-targeting drugs is currently being explored as an attractive alternative to combination therapy, especially for the treatment of complex diseases such as cancer. Dihydrofolate reductase (DHFR) and thioredoxin reductase (TrxR) are enzymes belonging to two unrelated cellular pathways that are known to contribute towards cancer cell growth and survival. In order to evaluate whether simultaneous inhibition of DHFR and TrxR by dihydrotriazines (DHFR-targeting) and chalcones (TrxR-targeting) may be beneficial, breast MCF-7 and colorectal HCT116 carcinoma cells were treated with combinations of selected dihydrotriazines and chalcones at a 1:1 M ratio. Two combinations demonstrated synergy at low-to-moderate concentrations. Based on this result, four merged dihydrotriazine-chalcone compounds were designed and synthesized. Two compounds, 11a [DHFR IC50 = 56.4 μM, TrxR IC50 (60 min) = 12.6 μM] and 11b [DHFR IC50 = 2.4 μM, TrxR IC50 (60 min) = 10.1 μM], demonstrated in vitro inhibition of DHFR and TrxR. The compounds showed growth inhibitory activity against MCF-7 and HCT116 cells, but lacked cytotoxicity. Molecular docking experiments showed 11b to possess rational binding modes to both the enzymes. In conclusion, this study has not only identified the dihydrotriazine and chalcone scaffolds as good starting points for the development of dual inhibitors of DHFR and TrxR, but also demonstrated the synthetic feasibility of producing a chemical entity that could result in simultaneous inhibition of DHFR and TrxR. Future efforts to improve the antiproliferative profiles of such compounds will look at alternative ways of integrating the two pharmacophoric scaffolds.
Synthesis of pyrazolopyrimidine derivatives along with its biological activity including toxicity studies
Singh,Gousuddin, Mohammad,Khan, Huma
, p. 182 - 200 (2021/02/27)
Pyrazolopyrimidines and related fused heterocycles are of interest as potential bioactive molecules. The heterocyclic fusion of pyrimidine ring and pyrazole ring resulted in formation of pyrazolopyrimidines, the structural analogues of biogenic purine class, undoubtedly, has high significance in the field of pharmaceutical and biotechnological sciences with wide spectrum of biological activities and its several derivatives. Toxicity may be due to the accumulation in a specific organ/ tissue (e.g. bosentan), the co - administration of other drugs affecting ADMET (absorption, distribution, metabolism, elimination and toxicity) Cmax reaching off target IC50, or the high Cmax required for therapeutic effects. Assessing the relative drug efficacy and toxicity is important for medicinal chemists, pharmacologists, pharmacists, physicians. As multiple treatment options are available for many diseases, relative toxicity assessment is necessary. Difficulty in direct clinical trial comparisons forces network meta-analyses for estimating the relative toxicity. Therapeutic index (TI) assumes simplified linear relationships between receptor affinity, maximum unbound plasma drug concentration (Cmax) and toxicity. But high TI does not guarantee safety. For drugs metabolized by cytochrome P450 (CYP450),estimating TI based on target potencies alone is insufficient.
