Synthesis and Biological Activity of Diastereomeric and Geometric Analogs of Calcipotriol, PRI-2202 and PRI-2205, Against Human HL-60 Leukemia and MCF-7 Breast Cancer Cells

Abstract

Diastereomeric and geometric analogs of calcipotriol, PRI-2202 and PRI-2205, were synthesized as advanced intermediates from vitamin D C-22 benzothiazoyl sulfones and side-chain aldehydes using our convergent strategy. Calcitriol, calcipotriol (PRI-2201) and tacalcitol (PRI-2191) were used as the reference compounds. Among a series of tested analogs the diastereomeric analog PRI-2202 showed the strongest antiproliferative activity on the human breast cancer cell line MCF-7, whereas the geometric analog PRI-2205 was the weakest. Both analogs were less potent in antiproliferative activity against HL-60 cells compared to the reference compounds. The ability to potentiate antiproliferative effect of cisplatin or doxorubicin against HL-60 cells or that of tamoxifen against the MCF-7 cell line was observed at higher doses of PRI-2202 or PRI-2205 than those of the reference compounds. The proapoptotic activity of tamoxifen, expressed as the diminished mitochondrial membrane potential, as well as the increased phosphatidylserine expression, was partially attenuated by calcitriol, PRI-2191, PRI-2201 and PRI-2205. The treatment of the MCF-7 cells with tamoxifen alone resulted in an increase in VDR expression. Moreover, a further increase in VDR expression was observed when the analogs PRI-2201 or PRI-2205, but not PRI-2191, were used in combination with tamoxifen. This observation could partially explain the potentiation of the antiproliferative effect of tamoxifen by vitamin D analogs.

Vitamin D in cancer chemoprevention

“…Experimental observations show that this molecule exerts important effects on cellular differentiation and proliferation in vitro while its effect on calcium metabolism in vivo is negligible (Binderup & Bramm, 1988;Cho et al, 1996). In vitro studies showed that this molecule may regulate cell differentiation and proliferation and exhibits growth-inhibiting effects against several human cancer cell lines including HL-60 and HL60/MX2 promyelocytic leukemia, U937 histiocytic lymphoma, MCF-7, T47D human breast cancer, HT-29 human colon cancer, and human SCC (Colston et al, 1992;Meephansan et al, 2012;Milczarek et al, 2013aMilczarek et al, , 2014. Regarding the possible mechanisms underlying the growth inhibiting and pro-differentiating effects of calcipotriol on tumor cells, in vitro studies highlighted the fact that a 20-h exposure of LNCaP prostate cancer cells and MCF-7 breast cancer cells to this analogue or to BGP-15, a new calcipotriene-derived vitamin D 3 analogue, generated procaspase-3 cleavage and ultimately, apoptosis (Berkovic et al, 2010).…”

Antiproliferative Activity and in Vivo Toxicity of Double-Point Modified Analogs of 1,25-Dihydroxyergocalciferol

“…Numerous in vitro and in vivo studies, demonstrating that calcitriol (1,25-dihydroxyvitamin D 3 ), an active hormonal form of vitamin D 3 , is an efficacious inhibitor of cancer cell proliferation, have supplied the justification for using this hormone in the treatment of patients suffering from leukemia and other types of cancer. It has been shown [ 3 , 4 , 5 , 6 , 7 ] that calcitriol or its analogs interact synergistically in the antitumor activity with some chemotherapeutic agents. This effect is frequently described as a result of calcitriol-induced cell differentiation [ 5 , 8 , 9 ].…”

“…What more, PRI-1907 is substantially more toxic than both calcitriol and PRI-1906 or PRI-2191 [ 5 ]. We have also identified a new calcipotriol derivative with diastereomeric and geometric modifications, PRI-2205, that shows a strong effect on the cell cycle, and antiproliferative activity in vitro [ 3 , 9 , 13 ], very low toxicity and antitumor activity in vivo [ 14 , 15 , 16 ].…”

Divergent Effect of Tacalcitol (PRI-2191) on Th17 Cells in 4T1 Tumor Bearing Young and Old Ovariectomized Mice

“…The data showing promotion of tumor growth and metastasis via vitamin D deficiency are presented also using xenografts of human breast cancer cell lines [22] and allografted mouse tumors [23][24][25]. The anticancer and antimetastatic activity of calcitriol or its analogs in various breast cancer models was also presented [26][27][28]. However, recent meta-analysis has shown that the significant protective effect of high serum 25-OH vitamin D can be detected only in premenopausal patients [29].…”