Further Synthetic and Biological Studies on Vitamin D Hormone Antagonists Based on C24-Alkylation and C2α-Functionalization of 25-Dehydro-1α-hydroxyvitamin D₃-26,23-lactones

Abstract

An efficient synthesis and the biological evaluation of 80 novel analogs of 25-dehydro-1alpha-hydroxyvitamin D3-26,23S-lactone 2 (TEI-9647) and its 23R epimer (3) in which the lactone ring was systematically functionalized by introduction of a C1 to C4 primary alkyl group at the C24 position (5 sets of 4 diastereomers), together with their C2alpha-methyl, 3-hydroxypropyl, and 3-hydroxypropoxy-substituted derivatives were described. The triene structure of the vitamin D3 was constructed using palladium-catalyzed alkenylative cyclization of the A-ring precursor enyne with the CD-ring counterpart bromoolefin having the C24-alkylated lactone moiety on the side chain. The CD-ring precursors having 23,24-cis lactones were prepared by using a chromium-mediated syn-selective allylation-lactonization process, and the 23,24-trans lactone derivatives were derived from these via inversion of the C23 stereochemistry. The biological evaluation revealed that both binding affinity for chick vitamin D hormone receptor and antagonistic activity (inhibition of vitamin D hormone induced HL-60 cell differentiation) were affected by the orientation and chain-length of the primary alkyl group on the lactone ring. Furthermore, the C2alpha-functionalization of the C24-alkylated vitamin D3 lactones dramatically enhanced their biological activities. The most potent compound to emerge, (23S,24S)-2alpha-(3-hydroxypropoxy)-24-propyl exhibited almost 1000-fold stronger antagonistic activity (IC50=7.4 pM) than 2 (IC50=6.3 nM).

3D‐QSAR Studies on C24‐Monoalkylated Vitamin D3 26,23‐Lactones and their C2α‐Modified Derivatives with Inhibitory Activity to Vitamin D Receptor

“…In the case of (23S, 24S) isomers (2, 6, and 18), their R 1 substituents are big enough to touch this green contour, which enhance their antagonistic activities to be 2.2, 3.5 and 1.7-fold higher potencies than that of 1. [28] We can see that this large green area lies just below the large yellow contours, indicating moderate groups are preferred to the inhibitory activity while bulky groups may touch the yellow polyhedron and decrease the activity. A case point is that compound 51 has a little stronger potency than that of 55.…”

“…Since the experimental values [28] were given as relative antagonistic activities, we converted them to the absolute values of IC 50 (in nM) based on the data of compounds 1 (IC 50 is 6.3 nM) and 13 (IC 50 is 0.0074 nM), as listed in Table 1. The converting details are described by the note in Table 1.…”

“…[15] Recently, people have paid much attention to vitamin D antagonists for their potential functions for some diseases (such as Paget's disease of bone) [23] induced by the hypersensitivity of VDR to the natural ligand. In order to look for more potential vitamin D 3 lactone analogs, Saito et al [24][25][26] and Nagasawa et al [27,28] have designed and synthesized a series of analogs of TEI-9647 and TEI-9648. They reported that the functionalizations of C2a and C24 positions could enhance the biological activities of vitamin D 3 lactones to a certain degree.…”

“…The established CoMFA model in training set gives a cross-validated q 2 value of 0.516 and a non-cross-validated r ncv 2 value of 0.667, while the CoMSIA model results in q 2 = 0.517 and r ncv 2 = 0.632. In general, the predictive ability of the CoMFA model is supe-study a series of chemically diverse C24-monoalkylated vitamin D 3 26,23-lactones and their C2a-modified derivatives [28] to investigate the influence of substituents and stereochemistry on the biological activities. Here, the 3D-QSAR model is established by using comparative molecular field analysis (CoMFA) [29] and comparative molecular similarity indices analysis (CoMSIA) [30] to find the common structural features among a series of vitamin D 3 26,23-lactone analogs.…”

Creative synthesis of novel vitamin D analogs for health and disease

“…Both vitamin D 3 analogs 15 and 16, which have an ␣-methylene-␥-butyrolactone part on the side-chain, are the first specific antagonists of VDR-mediated genomic action of 1, and 15 with 23S-configration has stronger antagonism (IC 50 9.4 nM) than 16 with 23R-configration (IC 50 134.3 nM). After our synthetic studies on the C2␣ and C24-double functionalization of 15 and 16 to investigate the structure-activity relationships, we found that 2␣-(3-hydroxypropoxy)-24-propyl-25-dehydro-1␣-hydroxyvitamin D 3 -26,23-lactone (17) showed the strongest VDR antagonism, as far as we know, and its IC 50 value was 7.4 pM to inhibit differentiation of human leukemia cells (HL-60 cells) induced by 10 nM of 1 [51].…”