Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Ciudad Universitaria, 72570 Puebla, Pue., Mexico.
Instituto de Física "Luis Rivera Terrazas" Benemérita Universidad Autónoma de Puebla Ecocampus Valsequillo, 72960 San Pedro Zacachimalpa, Pue., Mexico.
Molecules. 2019 Oct 12;24(20):3676. doi: 10.3390/molecules24203676.
A small and focused library of steroidal non-fused and fused pyrimidines was prepared from pregnenolone acetate and diosgenin, respectively. The key step was the cycloaddition reaction of nitrogen-containing 1,3-binucleophiles with the steroidal α,β-unsaturated ketone. Urea, thiourea and guanidine reacted in a similar manner and afforded the steroidal pyrimidines in good yields. The antiproliferative tests against human tumor cell lines gave GI values in the micromolar range and had no effect on healthy fibroblasts. Additional experiments indicated that the compounds did not act as P-glycoprotein substrates, thus avoiding the rise of drug resistance. The fused steroidal pyrimidinethione was selected as drug lead for further testing due to its strong antiproliferative activities within the low micromolar range.
从小而精的甾体非稠合和稠合嘧啶文库出发，分别从孕烯醇酮乙酸酯和薯蓣皂苷元合成而来。关键步骤是含氮 1,3-双亲核试剂与甾体 α,β-不饱和酮的环加成反应。脲、硫脲和胍以相似的方式反应，以良好的收率得到甾体嘧啶。对人肿瘤细胞系的抗增殖试验给出了微摩尔范围内的 GI 值，对健康成纤维细胞没有影响。进一步的实验表明，这些化合物不作为 P-糖蛋白底物，从而避免了耐药性的产生。由于稠合甾体嘧啶硫酮在低微摩尔范围内具有很强的抗增殖活性，因此被选为进一步测试的药物先导化合物。
