Biological Evaluation of Double Point Modified Analogues of 1,25-Dihydroxyvitamin D₂ as Potential Anti-Leukemic Agents

• Published in: International journal of molecular sciences Vol. 17; no. 2; p. 91
• Main Authors: Corcoran, Aoife, Nadkarni, Sharmin, Yasuda, Kaori, Sakaki, Toshiyuki, Brown, Geoffrey, Kutner, Andrzej, Marcinkowska, Ewa
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.02.2016; MDPI
• Subjects: Antagonist drugs; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Differentiation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor - methods; Ergocalciferols - chemistry; Ergocalciferols - pharmacology; HL-60 Cells; Humans; Leukemia; Leukemia - drug therapy; Leukemia - enzymology; Leukemia - metabolism; Molecular Structure; Pharmacology; receptor; Receptors, Calcitriol - metabolism; Structure-Activity Relationship; Substrate Specificity; Vitamin D; vitamin D analogues; Vitamin D3 24-Hydroxylase - antagonists & inhibitors; leukemia; vitamin D analogues; receptor
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms17020091

Structurally similar double-point modified analogues of 1,25-dihydroxyvitamin D₂ (1,25D₂) were screened in vitro for their pro-differentiating activity against the promyeloid cell line HL60. Their affinities towards human full length vitamin D receptor (VDR) and metabolic stability against human vitamin D 24-hydroxylase (CYP24A1) were also tested. The analogues (PRI-1730, PRI-1731, PRI-1732, PRI-1733 and PRI-1734) contained 5,6-trans modification of the A-ring and of the triene system, additional hydroxyl or unsaturation at C-22 in the side chain and reversed absolute configuration (24-epi) at C-24 of 1,25D₂. As presented in this paper, introduction of selected structural modifications simultaneously in two distinct parts of the vitamin D molecule resulted in a divergent group of analogues. Analogues showed lower VDR affinity in comparison to that of the parent hormones, 1,25D₂ and 1,25D₃, and they caused effective HL60 cell differentiation only at high concentrations of 100 nM and above. Unexpectedly, introducing of a 5,6-trans modification combined with C-22 hydroxyl and 24-epi configuration switched off entirely the cell differentiation activity of the analogue (PRI-1734). However, this analogue remained a moderate substrate for CYP24A1, as it was metabolized at 22%, compared to 35% for 1,25D₂. Other analogues from this series were either less (12% for PRI-1731 and PRI-1733) or more (52% for PRI-1732) resistant to the enzymatic deactivation. Although the inactive analogue PRI-1734 failed to show VDR antagonism, when tested in HL60 cells, its structure might be a good starting point for our design of a vitamin D antagonist.