Synthesis, antiproliferative and apoptosis-inducing activity of thiazolo[5,4-d]pyrimidines.
Singh B, Guru SK, Kour S, Jain SK, Sharma R, Sharma PR, Singh SK, Bhushan S, Bharate SB, Vishwakarma RA.
Thiazolo[5,4-d]pyrimidines are important class of heterocyclic compounds possessing diverse range of biological activities. Herein, we report an efficient synthesis of thiazolo[5,4-d]pyrimidines using recyclable KF/alumina catalyst. The reaction of 4,6-dichloro-5-aminopyrimidine with isothiocyanates in presence of 20 mol% KF/alumina produced thiazolo[5,4-d]pyrimidines in excellent yields without any chromatographic purifications. The method is operationally simple, fast and the catalyst can be reused without any significant loss of activity. These compounds were tested for antiproliferative activity in a panel of 8 cancer cell lines, including lung (NCI-H322 and A549), epidermal (A431), glioblastoma (T98G), pancreatic (MIAPaCa-2), prostate (PC-3), human leukemia (HL-60) and breast (T47D) cells. The N,N'-diethylamino-substituted analog, 2-(4-chlorophenylamino)-7-diethylamino-thiazolo[5,4-d]pyrimidine 4k showed antiproliferative activity in lung (NCI-H322 and A549), epidermal (A431) and glioblastoma (T98G) cancer cell lines with IC50 values of 7.1, 1.4, 3.1 and 3.4 μM, respectively. The morpholine substituted analog 4a displayed activity in HL-60 cells with IC50 value of 8 μM. The compound 4k showed induction of apoptosis in A549 cells at 10 μM, as indicated by the increase in the sub-G1 population. The nuclear morphology of A549 cells after treatment with 4k was also investigated. Similarly, the morpholine substituted analog 4a induced apoptosis in HL-60 cells at 20 μM. The effect of compound 4a on mitochondrial potential loss in HL-60 cells was also studied. Further, western blotting of 4a and 4k showed cleavage of PARP-1 and procaspase-3 inhibition which confirms their apoptosis-inducing activity.