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

Abstract

Analogs of 1,25-dihydroxyergocalciferol, modified in the side-chain and in the A-ring, were tested for their antiproliferative activity against a series of human cancer cell lines in vitro and in vivo toxicity. The proliferation inhibition caused by the analogs was higher than that of the parent compounds, while the toxicity, measured as the serum calcium level, was lower. All analogs were able to induce, in HL-60 and MV4-11 leukemic cells, G0/G1 cell cycle arrest and differentiation expressed as morphological signs typical for monocytes. The analogs also induced the expression of CD11b and/or CD14 cell-differentiation markers. The most potent analogs, PRI-5105, PRI-5106, PRI-5201 and PRI-5202, were also able to induce vitamin D receptor (VDR) protein expression, mainly in the cytoplasmic fraction of HL-60 or MV4-11 cells. The most active analogs were the 19-nor ones with an extended and rigidified side-chain (PRI-5201 and PRI-5202), as in the former analogs PRI-1906 and PRI-1907. Epimerization at C-24 (PRI-5101) or introduction of an additional hydroxyl at C-23 (PRI-5104) reduced the toxicity of the analog with retained antiproliferative activity.

Antiproliferative Activity of Double Point Modified Analogs of 1,25-Dihydroxyvitamin D2 Against Human Malignant Melanoma Cell Lines

“…Many studies have reported that the biological activities of 1,25(OH) 2 D 2 and 1,25(OH) 2 D 3 are very similar [ 45 ]. By contrast, the human malignant melanoma cell lines A375 and SK-MEL 188b, investigated in this study responded differently to the treatment with 1,25(OH) 2 D 3 and 1,25(OH) 2 D 2 .…”

“…Previously, we have investigated the activities of low calcemic analogs of vitamin D 3 with 20-hydroxyl, as well as analogs with a short side chain ([ 41 , 42 ], also see [ 40 , 43 ] for recent reviews). In our continuous search for more active vitamin D analogs for use as potential therapeutics [ 44 ], we have investigated the analogs of 1,25-dihydroxyvitamin D 2 (1,25(OH) 2 D 2 ) [ 45 ]. Following the discovery [ 46 ] of an ample free space around the terminal part of the side-chain we designed [ 47 ], synthesized [ 48 ] and investigated the biological activity of side-chain homologated analogs [ 49 ].…”

Prodifferentiation Activity of Novel Vitamin D2 Analogs PRI-1916 and PRI-1917 and Their Combinations with a Plant Polyphenol in Acute Myeloid Leukemia Cells

“…We have previously demonstrated that PRI-1906 and PRI-1907, the 1,25D2 analogs with extended and rigidified side-chains, exhibit increased anti-leukemia potency, as compared to 1,25D3 [ 27 , 30 ]. While PRI-1906 is substantially less calcemic than 1,25D3, the much stronger differentiation inducer PRI-1907 is also much more toxic [ 37 , 38 ]. To improve these lead compounds, we recently introduced the 19- nor modification of the A-ring of PRI-1906, resulting in PRI-5201 [ 28 ].…”

The Effect of Analogues of 1α,25-Dihydroxyvitamin D2 on the Regrowth and Gene Expression of Human Colon Cancer Cells Refractory to 5-Fluorouracil

“…Diluted solution of 5-FU was added to cell culture at a final concentration of 6 μg/mL (46 μM). 1,25D3, 1,25D2, PRI-2191 [(24 R )-1,24-dihydroxyvitamin D 3 , tacalcitol], PRI-1906, PRI-1907, PRI-1916, and PRI-1917 were synthesized at the Pharmaceutical Research Institute, Warsaw, Poland [ 62 , 63 , 64 , 65 ]. Samples of analogues were aliquoted to amber ampoules and dried down in a stream of argon.…”