Design, synthesis, evaluation and structure of Allenic 1α,25-Dihydroxyvitamin D3 analogs with locked mobility at C-17

Design, Synthesis, Evaluation and Structure of Allenic 1α,25-Dihydroxyvitamin D3Analogs with Locked Mobility at C-17 Ramón Fraga,[a] Kateryna Len,[b] Regis Lutzing,[b] Gilles Laverny,[b] Julian Loureiro,[c] Miguel A. Maestro,[a, d] Natacha Rochel,*[b] Enrique Rodriguez-Borges,*[c] and Antonio Mouriño*[a] In memory of Anthony Norman and Gary Posner. Abstract: Vitamin D receptor ligands have potential for the treatment of hyperproliferative diseases and disorders related to the immune system. However, hypercalcemic effects limit their therapeutical uses and call for the development of tissue-selective new analogs. We have designed and synthesized the first examples of 1α,25-dihydroxyvitamin D3analogs bearing an allenic unit attached to the D ring to restrict the side-chain conformational mobility. The triene system was constructed by a Pd0-mediated cyclization/Suzuki-Miyaura cross-coupling process in the presence of an allenic side chain. The allenic moiety was built through an orthoester- Claisen rearrangement of a propargylic alcohol. The biological activity and structure of (22S)-1α,25-dihydroxy-17,20-dien-24- homo-21-nor-vitamin D3bound to binding domain of the vitamin D receptor, provide information concerning sidechain conformational requirements for biological activity. Introduction The active form of the secosteroid hormone vitamin D3, 1α,25- dihydroxyvitamin D3[1, calcitriol, 1,25-(OH)2D3, 1,25D, Figure 1], exerts its biological functions by binding to the vitamin D receptor (VDR), a transcription factor of the nuclear receptor superfamily (NRs).[1] 1,25D was known for many years as a primary regulator of calcium homeostasis, but it also controls a wide range of other biological functions including cell differentiation, cell proliferation, and immune responses.[2,3] 1,25D induces the expression of more than 200 genes associated with several diseases such as arthritis, diabetes and cancer, suggesting that this secosteroid hormone might induce a wide range of biological functions.[4] Unfortunately, 1,25D induces hypercalce- [a] Dr. R. Fraga, Prof. M. A. Maestro, Prof. A. Mouriño Departamento de Química Orgánica Laboratorio de Investigación Ignacio Ribas Universidad de Santiago, Avda Ciencias s/n 15782 Santiago de Compostela (Spain) E-mail: [email protected] [b] K. Len, R. Lutzing, Dr. G. Laverny, Prof. N. Rochel Institut de Génétique et de Biologie, Moléculaire et Cellulaire (IGBMC) 67400 Illkirch (France) and Institut National de La Santé et de La Recherche Médicale (INSERM), U1258 67400 Illkirch (France) and Centre National de Recherche Scientifique (CNRS), UMR7104 67400 Illkirch (France) and Université de Strasbourg, 67400 Illkirch (France) E-mail: [email protected] [c] Dr. J. Loureiro, Prof. E. Rodriguez-Borges LAQV/REQUIMTE Departamento de Química e Bioquímica Faculdade de Ciências da Universidade do Porto (Portugal) E-mail: [email protected] [d] Prof. M. A. Maestro Departamento de Química-CICA Facultad de Ciencias Universidad de A Coruña Campus da Zapateira s/n, 15071 A Coruña (Spain) Supporting information for this article is available on the WWW under https://doi.org/10.1002/chem.202101578 © 2021 The Authors. Chemistry - A European Journal published by Wiley- VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Figure 1. Structures of the natural hormone 1,25D (1), 1,25D analogs 2a–2e, calcipotriol and maxacalcitol. Chemistry—A European Journal Full Paper doi.org/10.1002/chem.202101578 13384Chem. Eur. J. 2021,27, 13384–13389 © 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Mittwoch, 08.09.2021 2153 / 214082 [S. 13384/13389] 1 mia at the doses required for the treatment of hyperproliferative diseases such as cancer.[3] This limitation has led to intense synthetic efforts towards VDR ligands with selective activities as potential therapeutic agents for the treatment of cancer, immunodeficiency syndromes, autoimmune diseases and skin disorders.[5] Calcipotriol and maxacalcitol, examples of 1,25D analogs with a modified side-chain, exhibit similar or higher antiproliferative potency with reduced calcemic effects in comparison with natural hormone 1,25D (Figure 1).[6] Other potent 1,25D analogs structurally modified at the CD-rings or triene system that induce low potency for calcium metabolism have also been synthesized. Representative examples of these compounds include inecalcitol (19-nor-14-epi-23-yne-1,25D, TX522)[7] and PG-136,[8] which exhibit anticancer properties, and paricalcitol (19-nor-1,25D), which induces immunomodulatory effects and was recently proposed as a therapeutic option for patients with severe COVID-19.[9] Unfortunately, the mechanism underlying the dissociation of the antiproliferative effects from the calcemic effects, as well as the conformational requirements for selective biological functions, have not yet been established.[10] The crystallographic structures of 1,25D and various of its analogs in complex with the VDR ligand binding domain indicate that the corresponding side-chain-C25OH groups adopt similar positions.[11] However, the side-chain flexibility makes difficult to predict the conformation associated with a particular biological function. Okamura and coworkers, in efforts to understand structure-activity relationships, pioneered the synthesis of 1,25D analogs with rigid structural units at the side chain to restrict its conformational mobility.[12] In the search for vitamin D analogs with an even higher degree of restricted mobility of the side chain, we have started a research program on the synthesis and biological evaluation of 1,25D analogs with locked units at the side chains attached to the D-ring, in the form of double bond,[13] cyclopropane ring,[14] aromatic ring,[15] and triple bond.[16] In connection with this program, we describe here the development of the first side-chain analogs of 1,25D that incorporate an allenic unit at C17 as the structural element to impart restricted mobility to the side chain. Results and Discussion Design Based on the crystal structure of the active hVDR ligand-binding domain (LBD) bound to 1,25D,[11a] we studied the docking of the analogs 2a–2e bearing an allenic unit at the side chain attached to C17 of the D-ring (Figure 1). We showed that analog 2d binds well (97%) to the VDR LBD in comparison with the native hormone 1,25D (100%) (Figure 2). This analog adopts the canonical active conformation as the natural hormone in the binding pocked, where the A, C and D rings, and the triene system occupy similar positions. The A-ring and side-chain hydroxyl groups form effective hydrogen bonds with the same amino acid residues (His-305, His-397, Ser-278, Arg-274, Tyr-143, Ser-237) as the natural hormone. The other allenic analogs 2a (87%), 2b (92%), 2c (86%), and 2 e (84%) bind to the hVDR LBD less efficiently than 2d. On the basis of the in silico binding results, we chose compounds 2a,2b and 2d as the synthetic targets. Retrosynthetic analysis of target compounds The synthetic plan for the synthesis of target compounds 2a, 2b, and 2d is outlined in Scheme 1. The formation of the vitamin D triene system involves a stereoselective Pd0-catalyzed ring closure of enoltriflate 4and subsequent Suzuki-Miyaura coupling with unprotected alkenyl-boronic ester 3in protic medium following procedures developed in this laboratory.[17] At this point, the stability of the allenic unit under the Pdcatalyzed reaction conditions was uncertain. The boronates 3 are envisaged to arise from the allene 5by conventional Figure 2. A) Structure of the natural hormone 1,25D (yellow) in complex with hVDR LBD (PDB ID: 1DB1). B) Docked structure of analog 2d (magenta) into the hVDR LBD. C) Superimposition of both 1,25D and 2d. Ligand-amino acid distances are shown in Å. Chemistry—A European Journal Full Paper doi.org/10.1002/chem.202101578 13385Chem. Eur. J. 2021,27, 13384–13389 www.chemeurj.org © 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Mittwoch, 08.09.2021 2153 / 214082 [S. 13385/13389] 1 chemistry. The key allene 5would arise from propargylic alcohol 6through an orthoester-Claisen rearrangement.[18] Compound 6would be prepared in several steps by degradation of vitamin D2.[19] Synthesis of the upper boronate fragments The synthesis of boronates 3 a,3b, and 3 d is outlined in Scheme 2. Reaction of ketone 7with lithium trimethylsilylacetylide in THF followed by desilylation with Na2CO3in methanol provided propargylic alcohol 6[20] in 86% yield. Exposure of 6to orthoester Claisen rearrangement with triethyl orthoacetate and acetic acid delivered the (S)-allene 5(84%) as a single isomer [1H NMR δ5.27 (C=C=CH)]. Treatment of 5with methyl magnesium bromide in THF provided the tertiary alcohol 8a (98%), which was deprotected to alcohol 9a (98%) with tetrabutylammonium fluoride in THF. Pyridinium dichromate oxidation of 9a in CH2Cl2followed by Wittig-olefination of the resulting ketone 10a with ylide Ph3P=CHBr,[21] prepared from (Ph3PCH2Br)Br and KOtBu in toluene, led to (E)-alkenyl bromide 11a in 69% yield (two steps), which was converted to the desired upper boronate 3a (58% yield) without protection of the side-chain-hydroxyl group by Miyaura’s modified method[17,22] using bis(pinacolato)diboron and KOAc in the presence of catalytic [1,1’bis(diphenylphosphino) ferrocene] dichloropalladium(II) in DMSO. The synthesis of boronate 3d began with ester 5, which was converted to iodide 13 by a three steps sequence (81% yield) involving reduction with diisobutylaluminum hydride in THF, treatment of the resulting alcohol 12 with p-toluenesulfonyl chloride in pyridine, and subsequent reaction of the resulting Scheme 1. Retrosynthesis of target analogs 2 a,2b, and 2d from enoltriflate 4and propargylic alcohol 6. Scheme 2. Synthesis of the upper boronates 3a,3b, and 3d. Chemistry—A European Journal Full Paper doi.org/10.1002/chem.202101578 13386Chem. Eur. J. 2021,27, 13384–13389 www.chemeurj.org © 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Mittwoch, 08.09.2021 2153 / 214082 [S. 13386/13389] 1 tosylate with sodium iodide in acetone. Chain extension by reaction of iodide 13 with the lithium anion derived from tertbutyl acetate in THF provided ester 14 in 95% yield, which was converted to diol 16 (90%) by methylation (MeLi, THF) and subsequent deprotection (nBu4NF, THF). Pyridinium dichromate oxidation of 16 in CH2Cl2and subsequent Wittig-olefination of the resulting ketone 17 with ylide Ph3P=CHBr afforded the (E)- alkenyl bromide 18 in 82% yield (two steps), which was transformed into the desired upper boronate 3d (57% yield) by reaction with bis(pinacolato)diboron and KOAc in the presence of catalytic [1,1’bis(diphenylphosphino) ferrocene] dichloropalladium(II) in DMSO as above (23.3% overall yield from ketone 7, 12 steps). The allene moiety survived the Pd-catalyzed process during the formation of the vitamin D triene system though in moderate yield.[23] Synthesis of target compounds With the upper fragments in hand, we proceeded to the final convergent formation of the triene system of the target compounds 2a,2b, and 2d (Scheme 3). Pd-catalyzed carbocyclization of enoltriflate 4(1.1 equiv) and subsequent Suzuki- Miyaura coupling with boronate 3a (1 equiv) in the presence of catalytic bis(triphenylphosphine)palladium(II) in aqueous K3PO4 (2 M)/THF provided, after deprotection, the desired 1,25D- analog 2a in 51% yield (two steps) (13.7% overall yield from ketone 7, 14 steps). Same procedure was used for the preparation of allenic analog 2b (16.4% overall yield from ketone 7, 14 steps). In a similar way, Pd-catalyzed carbocyclization/Suzuki-Miyaura cross coupling tandem process on 3c provided the protected 1,25D-analog 19, which upon desilylation, gave the desired allenic 1,25D-analog 2d (54%, two steps) (14.5% overall yield from ketone 7, 14 steps). Functional activity As the in silico data indicate that the allene 2d binds to VDR with the highest efficiency, we determined its biological properties. Transactivation assay in HeLa cells transfected with human full length VDR showed that 1,25D (1) and 2d induce the expression of a luciferase reporter gene under the control of the promoter of human CYP24A1, the main vitamin D target gene (Figure 3, A). Note that at lower doses, 2d was less potent than 1. In addition, we monitor the expression of CYP24A1 transcripts in cells derived from prostate cancer metastasis (DU- 145) treated for 24 h. Ligands 2 d and 1induced transcript levels at 100 nM and 10 nM, but the levels were lower in cells treated with 2(Figure 3, B). To determine the effects of 2d in vivo, wild type mice were daily treated with various doses of 2 d and 1for 5 days. In agreement with previous results,[24] 1μg/kg of 1induced hypercalcemia and the transcript levels of the vitamin D target genes Cyp24a1 and S100g in the kidney (Figure 3, D–E). However, the renal transcript levels were similar in mice treated with 2d and with vehicle (Figure 3, D–E). The calcemic activity of 2d was evaluated by monitoring the serum calcium levels in the treated mice (Figure 3, C). Serum calcium levels were unaffected at 1 and 3 μg/kg. Thus, these results indicate that 2d is less potent than 1,25D, but behaves as a low-calcemic 1,25D analog. Crystal structure To determine the binding pose of the analog 2d, we cocrystallized the zebrafish wild-type VDR LBD[11c] in complex with Scheme 3. Synthesis of the target vitamin D analogs 2a,2b, and 2d. Figure 3. A) Transactivation assay in HeLa cells, transfected with full-length human VDR and a luciferase reporter gene under the control of the human CYP24A1 promoter, and treated for 24 h with 1,25D (1) or 2d at various concentrations. B) CYP24A1 transcript levels in DU-145 cells treated for 24 h with 1or 2d at various concentrations. EtOH was used as solvent (). Serum calcium levels (C) and renal transcript levels of Cyp24a1 (D) and S100g (E) determined in wild type mice, 6 h after 5 daily administrations of 2d or 1at the indicated doses. Oil was used as vehicle (0 or -). *p<0.05 vs. vehicle. Chemistry—A European Journal Full Paper doi.org/10.1002/chem.202101578 13387Chem. Eur. J. 2021,27, 13384–13389 www.chemeurj.org © 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Mittwoch, 08.09.2021 2153 / 214082 [S. 13387/13389] 1 the ligand and a coactivator peptide and solved the structure with a resolution up to 2.1 Å (Supporting Table 1). The overall structure is highly homologous to the VDR-1,25D structure with a root mean square deviation of 0.3 Å over 235 residues when comparing the Cαatoms of the two complexes. Superposition of the VDR ligand binding pocket in the presence of 2d and 1,25D shows similar positioning of the ligands (Figure 4, A), in agreement with the in silico docking data. The C1-OH, C3-OH and C25-OH groups of 2d form similar H-bonds as 1,25D (Figure 4A), however the C25-OH forms weaker H-bonds with His-333 and His-423 (3.2 Å and 3.0 Å for analog 2d compared to 2.8 Å and 2.8 Å for 1,25D). The secosteroidal part of the ligand forms similar interactions with the zVDR ligand binding pocket compared to 1,25D. The side chain of 2forms extensive interactions with Leu-255, Leu-258, Val-262, Ala-331, His-333, His-423, Tyr-427, Leu-430 at a 4.0 Å distance cutoff (Figure 4, B). The difference in side chain position as a consequence of the rigid allenic unit attached to C17, results in a loss of interaction to residue Leu-337 in complex with 2d. Overall, the contacts formed by 2d in the zVDR complex stabilize the agonist conformation of VDR in agreement with the agonist potency of this novel compound. The weaker hydrogen bonds with His- 333 and His-423 and loss of interaction with Leu-337 explain the observed difference in activity between the 1,25D and compound 2d. Conclusion In summary, we have designed and synthesized three analogs of the hormone 1α,25-dihydroxyvitamin D3bearing an allenic unit attached to C17 as the structural element to impart conformational rigidity near the D-ring. Highlights of the synthetic route (about 14% overall yield from bicyclic ketone 7, 14 steps), include the access to the allenic moiety by an orthoester-Claisen rearrangement and the formation of the triene system by a Pd0-catalyzed cyclization/cross coupling process involving an enoltriflate, precursor of the A-ring, and a vinyl boronate containing an allenic side-chain unit corresponding to the CD-Side chain framework. Biological evaluation of 2d with the highest affinity for VDR, reveals that the geometry imposed by the C17-allene moiety reduces the transcriptional potency and calcemic activity. The crystallographic structure of 2d in complex with the VDR LBD provides information concerning side-chain conformational requirements for the design of new noncalcemic vitamin D analogs of potential therapeutic interest. Experimental Section General: For details on the general materials and methods, see Supporting Information. Acknowledgements We thank FCT of Portugal (project PTDC/BIA-MIB/29059/2017), UIDB/50006/2020 to LAQV-REQUIMTE Research Unit, the European Union (European Regional Development Fund-ERDF), and Xunta de Galicia, Spain (GRC/ED431B/2018/13), for financial support. We also thank the Ligue contre le cancer, Agence Nationale de la Recherche ANR-13-BSV8-0024-01, and institucional funds from Instruct-ERIC for support and use of resources of the French Infrastructure for Integrated Structural Biology (ANR- 10-LABX-0030-INRT and ANR-10-IDEX-0002-02). 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