摘要
1α,25(OH)2D3,又称为活性维生素D3或骨化三醇,是维生素D3在体内发挥生理作用的基本形式。活性维生素D3除了具有调节钙磷代谢的功能外,还是一种细胞循环调节剂,影响细胞的增殖、分化和凋亡。它通过与维生素D受体(VDR)结合,在体内发挥多种多样的生理学功能,临床上可用来治疗骨质疏松、炎症、皮肤病、心血管疾病、癌症和免疫疾病等。
目前,我国仅有2个活性维生素D3类药物上市,分别是阿法骨化醇和骨化三醇,而二者均为第一代活性维生素D3类药物,由于它们是以维生素D3的活性形式在体内发生作用,各种生物作用相互交叉,长期使用会造成高血钙、高血钾等不良反应。马沙骨化醇(Maxacalcitol,OCT):由日本中外制药公司开发,其注射液(商品名Oxarol)于2000年上市,用于治疗肾透析患者的继发性甲状旁腺功能亢进症(SHPT);其软膏于2001年上市,商品名为Oxarol软膏,用于治疗银屑病等干癣类皮肤病。马沙骨化醇与VDR结合能力只是骨化三醇的1/7,但抑制甲状旁腺激素(PTH)的分泌作用与骨化三醇相当,诱导细胞分化的活性是骨化三醇的10倍,且钙代谢作用微弱,高血钙等不良反应较小。
慢性肾衰的发病率比较高。据专家估计,全国大约有几百万慢性肾衰患者。由于肾透析患者都存在活性维生素D3缺乏,并发展成继发性甲状旁腺功能亢进症,因此开发不良反应较少的活性维生素D3类药物马沙骨化醇,既能满足患者的需要,市场应用前景也十分广阔。银屑病等皮肤病也是危害人类健康、影响人类生活质量的一类重大疾病。据统计,在我国银屑病等皮肤病患者高达400万。在国外,活性维生素D3类药物已成为银屑病等皮肤病的首选药物,而中国目前在这领域仍是空白。治疗皮肤病药物马沙骨化醇的开发成功,将给众多皮肤病患者带来福音。
由于合成马沙骨化醇必需的手性原料须经微生物发酵而制备,国内外市场上均无销售,而这一技术和原料目前被日本中外制药公司所垄断。本研究以脱氢表雄酮为原料,经过TBS保护、魏悌希反应、硼氢化-氧化反应、脱掉TBS保护基、脱氢氧化、DHP保护20位羟基、环氧化、Li/NH3电子还原在1位引入了1α-羟基,TBS保护1,3位羟基,选择性脱掉THP保护基、Williamson反应、还原开环引入侧链,经NBS溴代、脱溴、脱掉1,3位TBS保护基、光化学反应、加热重排,最终制得马沙骨化醇。以脱氢表雄酮为原料经乙二醇保护17位羰基、脱氢氧化、环氧化、Li/NH3电子还原、脱掉乙二醇保护基后,我们合成了手性关键中间体1α-羟基脱氢表雄酮。我们开发的化学合成马沙骨化醇和1α-羟基脱氢表雄酮的新方法、新工艺,不但能打破国外的垄断,也将促进我国活性维生素D3类药物的研究,使我国在活性维生素D3类药物研究领域在世界上占有一席之地,为开发具有我国自主知识产权的活性维生素D3类一类新药奠定基础。
1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3], or calcitriol, the hormonally active metabolite of vitamin D3, functionizes as a regulator of calcium and phosphorus homeostasis, simultaneously is well recognized as an important cell cycle regulator. Therefore, 1α,25-Dihydroxyvitamin D3 can influence cell proliferation, differentiation and apotosis. 1α,25(OH)2D3 and its anologues exert their functions by binding to the vitamin D receptor (VDR), and have been used or have high potential for application as drugs in treating a diverse range of human diseases such as osteoporosis, inflammation, dermatological indication, cardiovascular diseases, cancers and autoimmune diseases and so on.
At present, alfacalcidol and calcitriol have been in clinical use in China. Since alfacalcidol is converted into calcitriol in the body, they exhibit the same biological activities and have the side effects like increasing the blood calcium and potassium levels. Maxacalcitol, developed by Chugai Pharmaceutical Co., Ltd, was launched as the brand name of Oxarol injection for the treatment of secondary hyperparathyroidism (SHPT) in 2000 and Oxarol ointment for psoriasis in 2001, in Japan. Maxacalcitol has high cell differentiating activity (10-fold activation) but has little affinity (about 1/7) for VDR, as compared to calcitriol. It also has the similar activity in suppressing the secrection of parathyroid hormone (PTH) with calcitriol and has poor calcemic activity.
Chronic Renal Failure (CRF) has a high mobility, and there are several millions patients in China. It is not unusual for people with chronic kidney failure to have low levels of vitamin D3, which subsequently cause secondary hyperparathyroidism. Thus, the development of maxacalcitol will meet the requirement of the patients of CRF in China. Psoriasis has been shown to affect health-related quality of life to a great extent. Patients with psoriasis have been estimated more than four millions in China. Active vitamin D3 analogues have been used as the primary drugs for the treatment of psoriasis in abroad. However, it is still applied in China. Developing maxacalcitol will be of great benefit to patients with psoriasis.
la-Hydroxydehydroepiandrosterone, the important building block for the preparation of maxacalcitol, is reported to be obtained from dehydroepiandrosterone (DHEA) by microbial oxidation. However, this material is not commercial available from the market. We report here a new synthetic route to maxacalcitol from DHEA. Protection of 3β-hydroxyl in DHEA as a TBS ether, followed by Wittig reaction and hydroboration-oxidation, generated the 20-hydroxyl intermediate. After the removal of TBS protective group and DDQ oxidation, the 20-hydroxyl group was protected with THP. Epoxide formation and reductive opening of the epoxide and isomerization with lithium in liquid ammonia, 1α-hydroxyl was introduced in the steroid A-ring. Protection of both 1α- and 3β-hydroxyl with TBS groups, followed by the selective removal of DHP group, Williamson ether formation, and reductive opening of the epoxide, the side chain of maxacalcitol was introduced. After bromination with NBS and debromination with y-collidine, the diene was formed. Removal of TBS groups, followed by UV irradiation and the thermal reaction, maxacalcitol was obtained successfully.
We also set up a new synthetic route to la-hydroxydehydroepiandrosterone, the important building block for the preparation of active vitamin D analogues. Ethylene ketal formation protected the keto group in DHEA. A novel palladium catalyzed dehydrogenation led to the enone, which undergoes epoxidation and reductive reaction with lithium in liquid ammonia to introduce the 1α-hydroxyl group. Subsequent acetal hydrolysis led to 1α-hydroxydehydroepiandrosterone. This novel syhthesis of 1α-hydroxydehydroepiandrosterone will provide the useful intermediate both for the synthesis of many active vitamin D3 drugs and novel selective vitamin D derivatives.
引文
[1]俞银芳,刘兆鹏。活性维生素D3类药物研究概况。中国药物化学杂志,2006,16,311-315。
[2]DeLuca H.F.; Schnoes H.K. Metabolism and mechanism of action of vitamin D. Ann. Rev. Biochem.,1976,45,631-666.
[3]Deeb, K.K.; Trump, D.L.; Johnson, C.S. Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat. Rev. Can.,2007,7,684-700.
[4]曾友元,刘佩玲。1,25一二羟维生素D3研究及应用进展。医师进修杂志,1997,20,159-161。
[5]Rochel N.; Wurtz J.M.; Mitschler A.; Klaholz B.; Moras D. The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. Molecular Cell, 2000,5,173-179.
[6]Yamada S.; Shimizu M.; Yamamoto K. Structure-function relationships of vitamin D including ligand recognition by the vitamin D receptor. Med. Res. Rev.,2003, 23,89-115.
[7]钱国锋,张秀珍。维生素D受体基因与骨质疏松症。现代医学,2003,31,277-280。
[8]余健,聂国明。维生素D3的免疫调节作用。国外医学：免疫学分册,2004,27,328-331。
[9]骆文静。维生素D及其类似物抗肿瘤作用机制。国外医学：肿瘤学分册,2004,31,425-427。
[10]朱汉民。1,2-羟化维生素D3和骨质疏松。国外医学：内分泌学分册,2003,23,119-122。
[11]Tan A.U. Jr; Levine B.S.; Mazess R.B.; Kyllo D.M.; Bishop C.W.; Knutson J.C.; Kleinman K.S.; Coburn J.W. Effective suppression of parathyroid hormone by 1 alpha-hydroxyvitamin D2 in hemodialysis patients with moderate to severe secondary hyperparathyroidism. Kidney Int.,1997,51,317-323.
[12]Martin K.J.; Gonzalez E.A. Strategies to minimize bone disease in renal failure. Am. J. Kidney Dis.,2001,38,1430-1436.
[13]樊平申,高天文。活性型维生素D3外用治疗银屑病。日本医学介绍,2004,25,422-423。
[14]Rostand S.G.; Drueke T.B. Parathyroid hormone, vitamin D, and cardiovascular disease in chronic renal failure. Kidney Int.,1999,56,383-392.
[15]Nishizawa Y.; Shoji T.; Kawagishi T.; Morii H. Atherosclerosis in uremia: Possible roles of hyperparathyroidism and intermediate density lipoprotein accumulation. Kidney Int.,1997,52,90-92.
[16]Mak R.H.K.1,25-dihydroxyvitamin D3 corrects insulin and lipid abnormalities in uremia. Kidny Int.,1998,53,1353-1356.
[17]Schwarz U.; Amann K.; Orth S.R.; Simonaviciene A.; Wessels S.; Ritz E. Effect of 1,25(OH)2D3 on glomerulosclerosis in subtotally nephrectomized rats. Kidney Int.,1998,53,1696-1705.
[18]Panichi V.; Migliori M.; Taccola D.; Filippi C.; De Nisco L.; Giovannini L.; Palla R.; Tetta C.; Camussi G Effects of 1,25(OH)2D3 in experimental mesangial proliferative nephritis in rats. Kidney Int.,2001,60,87-95.
[19]Makibayashi K.; Tatematsu M.; Hirata M.; Fukushima N.; Kusano K.; Ohashi S.; Abe H.; Kuze K.; Fukatsu A.; Kita T.; Doi T. A vitamin D analog ameliorates glomerular injury on rat glomerulonephritis. Am. J. Pathol.,2001,158, 1733-1741.
[20]Zhang Z. Renoprotective role of the vitamin D receptor in diabetic nephropathy. Kidney Int.,2008,73,163-171.
[21]Li C. Vitamin D and diabetic nephropathy. Curr. Diab. Rep.,2008,8,464-469.
[22]Linker-Israeli M.; Elstner E.; Klinenberg J.R.; Wallace D.J.; Koeffler H.P. Vitamin D3 and its synthetic analogs inhibit the spontaneous in vitro immunoglobulin production by SLE-derived PBMC. Clin. Immunol.,2001,99, 82-93.
[23]Nagakura K.; Abe E.; Suda T.; Hayakawa M.; Nakamura H.; Tazaki H. Inbibitory effect of 1 alpha,25-dihydroxyvitamin D3 on the growth of the renal carcinoma cell line. Kidney Int.,1986,29,834-840.
[24]Ravid A.; Koren R. The role of reactive oxygen species in the anticancer activity of vitamin D. Recent Results Cancer Re.,2003,164,357-367.
[25]Jones G.; Strugnell S.A.; Deluca H.F. Current understanding of the molecular action of vitamin D. Physiol Rev.,1998,78,1193-1231.
[26]Deluca H.F.; Cantorna M.T. Vitamin D:its role and uses in immunology. FASEB J.,2001,15,2579-2585.
[27]Von Essen M.R.; Kongsbak R.; Schjerling P.; Olgaard K.;Φdum N.; Geisler C. Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nat. Immunol.,2010,11,344-350.
[28]Chen T.C.; Persons K.; Uskokovic M.R.; Horst R.L.; Holick M.F. An evaluation of 1,25-dihydroxyvitamin D3 analogues on the proliferation and differentiation of cultured human keratinocytes, calcium metabolism and the differentiation of human HL-60 cells. J. Nutr. Biochem.,1993,4,49-57.
[29]Mayer E.; Bishop J.E.; Chandraratna R.A.; Okamura W.H.; Kruse J.R.; Popjak G.; Ohnuma N.; Norman A.W. Studies on the metabolism of calciferol. XXIV. Isolation and identification of 1,25-dihydroxy-24-oxo-vitamin-D3 and 1,23,25-trihydroxy-24-oxo-vitamin-D3. New metabolites of vitamin-D3 produced by a C-24 oxidation pathway of metabolism for 1,25-dihydroxyvitamin D3. J. Biol. Chem.,1983,258,13458-13465.
[30]Ostrem V.K.; Lau W.F.; Lee S.H.; Perlman K.; Prahl J.; Schnoes H.K.; DeLuca H.F. Induction of monocytic differentiation of HL-60 cells by 1, 25-dihydroxyvitamin D analogs.J. Biol. Chem.,1987,262,4164-4171.
[31]Siebert P.D.; Ohnuma N.; Norman A.W. Studies on the mode of action of calciferol. XXII. A 24R-hydroxyl-group can replace the 25-hydroxyl-group of la,25-dihydroxyvitamin D3 for optimal binding to the chick intestinal receptor. Biochem. Biophys. Res. Commun.,1979,91,827-834.
[32]Zhao X.Y.; De Clercq P.; Vandewalle M.; Allewaert K.; Van Baelen H.; Bouillon R. Synthesis and biological evaluation of some 25,26-epoxy-la,24-dihydroxyvitamin D3 analogues. Bioorg. Med. Chem. Lett., 1993,3,1863-1867.
[33]Allewaert K.; Zhao X.Y.; Zhao J.; Glibert F.; Branisteanu D.; De Clereq P.; Vandewalle M.; Bouillon R. Biological evaluation of epoxy analogs of 1α,25-dihydroxyvitamin D3. Steroids,1995,60,324-332.
[34]Bishop J.E.; Collins E.D.; Okamura W.H.; Norman A.W. Profile of ligand specificity of the vitamin D binding protein for 1,25(OH)2D3 and its analogs. J. Bone Miner. Res.,1994,9,1277-1288.
[35]Craig A.S.; Norman A.W.; Okamura W.H. Studies of vitamin-D (calciferol) and its analogues. ⅩⅩⅩⅩⅢ.2 Novel allenic side chain analogues of 1α,25-dihydroxyvitamin D3. J. Org. Chem.,1992,57,4374-4380.
[36]Koizumi T.; Nakao Y.; Ishizuka S.;, Oshida J.; Hara N.; Ikekawa N.; Fijita T. Novel vitamin D3 derivatives,26-homo-22-dehydro 1α,25(S)-dihydroxyvitamin D3 and 26-homo-22-dehydro-1α,25(R)-dihydroxyvitamin D3:preferential activity in c-myc mRNA production and in induction of phenotypic differentiation of HL-60 cells. Arch. Biochem. Biophys.,1990,276,310-316.
[37]Sai H.; Takatsuto S.; Ikekawa N.; Tanaka Y. Synthesis and biological-activity of (22E,24R) and (22E,24S)-1α,24-dihydroxy-22-dehydrovitamin D3. Chem. Pharm. Bull.,1984,32,3866-3872.
[38]Jehan F.; Neveu I.; Barbot N.; Binderup L.; Brachet P.; Wion D. MC903, an analogue of 1,25-dihydroxyvitamin D3, increases the synthesis of nerve growth factor. Eur. J. Pharmacol. Mol. Pharmacol.,1991,208,189-191.
[39]Uskokovic M.R.; Baggiolini E.; Shiuey S.J.; Iacobelli J.; Hennessy B.; Kiegiel J.; Daniewski A.R.; Pizzolato G.; Coustney L.F.; Horst R.L. The 16-ene-analogs of 1,25-dihydroxycholecalciferol synthesis and biological activity. In:Norman A.W.; Bouillon R.; Thomasset M(eds). Vitamin D:Gene regulation, rtructure-function analysis and clinical application. Walter de Gruyter, Berlin, 1991,139-145.
[40]Norman A.W.; Sergeev I.N.; Bishop J.E.; Okamura W.H. Selective biological response by target organs (intestine, kidney and bone) to 1,25-dihydroxyvitamin D3 and two analogues. Cancer Res.,1993,53,3935-3942.
[41]Norman A.W.; Zhou J.; Henry H.L.; Uskokovic M.R.; Koeffler H.P. Structure-function studies on analogues of 1α,25-dihydroxyvitamin D3: differential effects on leukemic cell growth, differentiation, and intestinal calcium absorption. Cancer Res.,1990,50,6857-6864.
[42]Zhou J.Y.; Norman A.W.; Akashi M.; Chen D.L.; Uskokovic M.R.; Aurrecoechea J.M.; Dauben W.G.; Okamura W.H.; Koeffler H.P. Development of a novel 1,25(OH)2-vitamin D3 analog with potent ability to induce HL-60 cell differentiation without modulating calcium metabolism. Blood,1991,78,75-82.
[43]Shiina Y.; Abe E.; Miyaura C.; Tanaka H.; Yamada S.; Ohmori M.; Nakayama K.; Takayama H.; Matsunaga I.; Nishii Y.; DeLuca H.F.; Suda T. Biological activity of 24,24-difluoro-1α,25-dihydroxyvitamin D3 and la,25-dihydroxyvitamin D3-26,23-lactone in inducing differentiation of human myeloid leukemia cells. Arch. Biochem. Biophys.,1983,220,90-94.
[44]Honda A.; Nakashima N.; Mori Y.; Katsumata T.; Ishizuka S. Effects of vitamin D-binding proteins on HL-60 cell differentiation induced by 26,26,26,27,27,27-hexafluoro-1α,25-dihydroxyvitamin D3. J. Steroid. Biochem. Mol. Biol.,1992,41,109-112.
[45]Honda A.; Nakashima N.; Shida Y.; Mori Y.; Nagata A.; Ishizuka S. Modification of 1α,25-dihydroxyvitamin D3 metabolism by introduction of 26,26,26,27,27,27-hexafluoro atoms in human promyelocytic leukaemia (HL-60) cells:isolation and identification of a novel bioactive metabolite, 26,26,26,27,27,27-hexafluoro la,23(S),25-trihydroxyvitamin D3. Biochem. J., 1993,295,509-516.
[46]Brown A.J.; Ritter C.R.; Finch J.L.; Morrissey J.; Martin K.J.; Murayama E.; Nishii Y.; Slatopolsky E. The noncalcemic analogue of vitamin D, 22-oxacalcitriol, suppresses parathyroid hormone synthesis and secretion. J. Clin. Invest.,1989,84,728-732.
[47]Kubodera N.; Miyamoto K.; Ochi K.; Matsunaga I. Synthetic studies of vitamin-D analogs. Ⅶ. Synthesis of 20-oxa-21-norvitamin-D3 analogs. Chem. Pharm. Bull.,1986,34,2286-2289.
[48]Kubodera N.; Miyamoto K.; Matsumoto M.; Kawanishi T.; Ohkawa H.; Mori T. Synthetic studies of vitamin-D analogues. Ⅹ. Synthesis and biological activities of 1α,25-dihydroxy-21-norvitamin-D3. Chem. Pharm. Bull.,1992,40,648-651.
[49]Kubodera N.; Miyamoto K.; Akiyama M.; Matsumoto M.; Mori T. Synthetic studies of vitamin-D analogues. Ⅸ. Synthesis and differentiation-inducing activity of 1α,25-dihydroxy-23-oxa-vitamin-D, thia-vitamin-D, and azavitamin-D3. Chem. Pharm. Bull.,1991,39,3221-3224.
[50]Allewaert K.; Convents R.; Biauw K.T.; Marcelis S.; Zhao G.; Zhao X.Y.; De Clercq P.; Vandewalle M.; Bouillon R. The biological activity of 23-oxa-, 23-oxa-24-oxo-, and 23-thia-dihydroxyvitamin D3. Steroids,1994,59,686-690.
[51]Binderup L.; Latini S.; Binderup E.; Bretting C.; Calverley M.; Hansen K. 20-Epi-vitamin D3 analogues:A novel class of potent regulators of cell growth and immune responses. Biochem. Pharmacol.,1991,42,1569-1575.
[52]Kubodera N.; Watanabe H.; Kawanishi T.; Matsumoto M. Synthetic studies of vitamin D-analogues. Ⅺ. Synthesis and differentiation-inducing activity of 1α,25-dihydroxy-22-oxavitamin-D3 analogues. Chem. Pharm. Bull.,1992,40, 1494-1499.
[53]Kahraman M.; Sinishtaj S.; Dolan P.M.; Kensler T.W.; Peleg S.; Saha U.; Chuang S.S.; Bernstein G.; Korczak B.; Posner G.H. Potent, selective and low-calcemic inhibitors of CYP24 hydroxylase:24-sulfoximine analogues of the hormone 1α,25-dihydroxyvitamin D3. J. Med. Chem.,2004,47,6854-6863.
[54]Binderup L. Immunological properties of vitamin D analogues and metabolites. Biochem. Pharmacol.,1992,43,1885-1892.
[55]Ostrem V.K.; Lau W.F.; Lee S.H.; Perlman K.; Prahl J.; Schnoes H.K.; DeLuca H.F. Induction of monocytic differentiation of HL-60 cells by 1,25-dihydroxyvitamin D analogs. J. Biol. Chem.,1987,262,4164-4171.
[56]Wecksler W.R.; Norman A.W. Structural aspects of the binding of 1α,25-dihydroxyvitamin D3 to its receptor system in chick intestine. Methods Enzymol.,1980,67,494-500.
[57]Ikekawa N. Chemical synthesis of vitamin D analogs with selective biological activities. In:Norman A.W.; Schaefer K.; Grigoleit H.G.; v Herrath D (eds). Vitamin D:Molecular, cellular and clinical endocrinology. Walter de Gruyter, Berlin,1988,25-33.
[58]Ostrem V.K.; Tanaka Y.; Prahl J.; DeLuca H.F.; Ikekawa N.24- and 26-homo-1,25-dihydroxyvitamin-D3:preferential activity in inducing differentiation of human-leukemia cells HL-60 in vitro. Proc. Natl. Acad. Sci., 1987,84,2610-2614.
[59]Perlman K.; Kutner A.; Prahl J.; Smith C.; Inaba M.; Schnoes H.K.; DeLuca H.F. 24-Homologated 1,25-dihydroxyvitamin D3 compounds:separation of calcium and cell differentiation activities. Biochemistry,1990,29,190-196.
[60]Honda A.; Mori Y.; Otomo S.; Ishizuka S.; Ikekawa N. Effects of novel 26,27-dialkyl analogs of 1α,25-dihydroxyvitamin D3 on differentiation-inducing activity of human promyelocytic leukemia (HL-60) cells in serum-supplemented or serum-free culture. Steroids,1991,56,142-147.
[61]Honda A.; Mori Y.; Ikekawa N.; Raz A. Manipulation of thromboxane synthesis by novel 26,27-dialkyl analogues of la,25-dihydroxyvitamin D3 in human promyelocytic leukemia (HL-60) cells. Eur. J. Pharmacol.,1992,229,217-222.
[62]Miyahara T.; Harada M.; Miyata M.; Sugure A.; Ikemoto Y.; Takamura T. Higuchi S.; Otomo S.; Kozuka H.; Ikekawa N. Calcium regulating activity of 26,27-dialkyl analogs of 1α,25-dihydroxyvitamin D3. Calcif. Tissue Int.,1992,51, 218-222.
[63]Saito N.; Honzawa S.; Kittaka A. Recent Results on A-Ring Modification of 1α,25-Dihydroxyvitamin D3:Design and synthesis of VDR-agonists and antagonists with high biological activity. Curr. Top. Med. Chem.,2006,6, 1273-1288.
[64]Norman A.W.; Manchand P.S.; Uskokovic M.A.R.; Okamura W.H.; Takeuchi J.A.; Bishop J.E.; Hisatake J.I.; Koeffler H.P.; Peleg S. Characterization of a novel analogue of 1α,25(OH)2-vitamin D3 with two side chains:interaction with its nuclear receptor and cellular actions. J. Med. Chem.,2000,43,2719-2730.
[65]Hisatake J.I.; O'Kelly J.; Uskokovic M.R.; Tomoyasu S.; Koeffler H.P. Novel vitamin D3 analog,21-(3-methyl-3-hydroxy-butyl)-19-nor D3, that modulates cell growth, differentiation, apoptosis, cell cycle, and induction of PTEN in leukemic cells. Blood,2001,97,2427-2433.
[66]Grue-Surensen G.; Hansen C.M. New 1α,25-dihydroxy vitamin D3 analogues with side chains attached to C-18:synthesis and biological activity. Bioorg. Med. Chem.,1998,6,2029-2039.
[67]Moman E.; Nicoletti D.; Mourino A. Synthesis of novel analogues of 1α,25-dihydroxyvitamin D3 with side chains at C-18. J. Org. Chem.,2004,69, 4615-4625.
[68]Roodman, G.D.; Windle, J.J. Paget disease of bone. J. Clin. Invest.,2005,115, 200-208.
[69]Reddy, S.V.; Kurihara, N.; Menaa, C.; Roodman, G.D. Paget's disease of bone:a disease of the osteoclast. Rev. Endocr. Metab. Disord.,2001,2,195.
[70]Ishizuka S.; Miura D.; Ozono K.; Saito M.; Eguchi H.; Chokki M.; Norman A.W. (23S)- and (23R)-25-dehydro-la-hydroxyvitamin D3-26,23-lactone function as antagonists of vitamin D receptor-mediated genomic actions of 1α,25-dihydroxyvitamin D3. Steriods,2001,66,227-237'.
[71]Miura D.; Manabe K.; Gao Q.; Norman A.W.; Ishizuka S. 1α, 25-dihydroxyvitamin D3-26,23-lactone analogs antagonize differentiation of human leukemia cells (HL-60 cells) but not of human acute promyelocytic leukemia cells (NB4 cells). FEBS Lett.,1999,460,297-302.
[72]Nakano Y.; Kato Y.; Imai K.; Ochiai E.; Namekawa J.I.; Ishizuka S.; Takenouchi K.; Tanatani A.; Hashimoto Y.; Nagasawa K. Practical Synthesis and evaluation of the biological activities of 1α,25-dihydroxyvitamin D3 antagonists, 1α,25-dihydroxyvitamin D3-26,23-lactams. Designed on the basis of the helix 12-folding inhibition hypothesis. J. Med. Chem.,2006,49,2398-2406.
[73]Kato Y.; Nakano Y.; Sano H.; Tanatani A.; Kobayashi H.; Shimazawa R.; Koshino H.; Hashimoto Y.; Nagasawa K. Synthesis of 1α,25-dihydroxyvitamin D3-26,23-lactams (DLAMs), a novel series of 1 a,25-dihydroxyvitamin D3 antagonist. Bioorg. Med. Chem.,2004,14,2579-2583.
[74]Kato Y.; Hashimoto Y.; Nagasawa K. Novel heteroatom-containing vitamin D3 analogs:efficient synthesis of 1α,25-Dihydroxyvitamin D3-26,23-lactam. Molecules,2003,8,488-499.
[75]Norman A.W.; Nemere I.; Muralidharan R.K.; Okamura W.H. 1 a,25(OH)2-vitamin D3 is an antagonist of 1α,25(OH)2-vitamin D3 stimulated transcaltachia (the rapid hormonal stimulation of intestinal calcium transport). Biochem. Biophys. Res. Commun.,1992,189,1450-1456.
[76]Norman A.W.; Bouillon R.; Farach-Carson M.C.; Bishop J.E.; Zhou L.X.; Nemere I.; Zhao J.; Muralidharan R.K.; Okamura W.H. Demonstration that 1 a,25-dihydroxyvitamin D3 is an antagonist of the nongenomic but not genomic biological responses and biological profile of the three A-ring diastereomers of 1α,25-dihydroxyvitamin D3. J. Biol. Chem.,1993,268,20022-20030.
[77]Konno, K.; Fujishima, T.; Maki, S.; Liu, Z.P.; Miura, D.; Chokki, M.; Ishizuka, S.; Yamaguchi, K.; Kan, Y.; Kurihara, M.; Miyata, N.; Smith, C.; DeLuca, H.F.; Takayama, H. Synthesis, biological evaluation, and conformational analysis of A-ring diastereomers of 2-methyl-1,25-dihydroxyvitamin D3 and their 20-epimers:nnique activity profiles depending on the stereochemistry of the A-ring and at C-20. J. Med. Chem.,2000,43,4247-4265.
[78]Fujishima, T.; Kittaka, A.; Yamaoka, K.; Takeyama, K.; Kato, S.; Takayama, H. Synthesis of 2,2-dimethyl-1,25-dihydroxyvitamin D3:A-ring structural motif that modulates interactions of vitamin D receptor with transcriptional coactivators. Org. Biomol. Chem.,2003,1,1863-1869.
[79]Fujishima, T.; Kittaka, A.; Kurihara, M.; Saito, N.; Honzawa, S.; Kishimoto, S.; Sugiura, T.; Waku, K.; Takayama, H.2,2-functionalized analogues of 1α,25-dihydroxyvitamin D3, the potent inducers of cell differentiation. J. Steroid. Biochem. Mol. Biol.,2004,89-90,89-92.
[80]Posner, G.H.; Woodard, B.T.; Crawford, K.R.; Peleg, S.; Brown, A.J.; Dolan, P.; Kensler, T.W.2,2-disubstituted analogues of the natural hormone 1 a,25-dihydroxyvitamin D3:chemistry and biology. Bioorg. Med. Chem.,2002, 10,2353-2365.
[81]Suhara, Y.; Nihei, K.; Tanigawa, H.; Fujishima, T.; Konno, K.; Nakagawa, K.; Okano, T.; Takayama, H. Syntheses and biological evaluation of novel 2α-substituted 1α,25-dihydroxyvitamin D3 analogues. Bioorg. Med. Chem. Lett., 2000,10,1129-1132.
[82]Suhara, Y.; Nihei, K.; Kurihara, M.; Kittaka, A.; Yamaguchi, K.; Fujishima, T. Konno, K.; Miyata, N.; Takayama, H. Efficient and versatile synthesis of novel 2α-substituted 1α,25-dihydroxyvitamin D3 analogues and their docking to vitamin D receptors. J. Org. Chem.,2001,66,8760-8771.
[83]Suhara, Y.; Kittaka, A.; Kishimoto, S.; Calverley, M.J.; Fujishima, T.; Saito, N.; Sugiura, T.; Waku, K.; Takayama, H. Synthesis and testing of 2a-modified 1α,25-dihydroxyvitamin D3 analogues with a double side chain:marked cell differentiation activity. Bioorg. Med. Chem. Lett.,2002,12,3255-3258.
[84]Honzawa, S.; Suhara, Y.; Nihei, K.; Saito, N.; Kishimoto, S.; Fujishima, T.; Kurihara, M.; Sugiura, T.; Waku, K.; Takayama, H.; Kittaka, A. Concise synthesis and biological activities of 2a-alkyl- and 2α-(ω-hydroxyalkyl)-20-epi-la,25-dihydroxyvitamin D3. Bioorg. Med. Chem. Lett.,2003,13, 3503-3506.
[85]Kittaka, A.; Suhara, Y.; Takayanagi, H.; Fujishima, T.; Kurihara, M.; Takayama, H. A Concise and efficient route to 2α-(ω-hydroxyalkoxy)-1α,25-dihydroxyvitamin D3:remarkably high affinity to vitamin D receptor. Org. Lett.,2000,2,2619-2622.
[86]Saito, N.; Suhara, Y.; Kurihara, M.; Fujishima, T.; Honzawa, S.; Takayanagi, H.; Kozono, T.; Matsumoto, M.; Ohmori, M.; Miyata, N.; Takayama, H.; Kittaka, A. Design and efficient synthesis of 2α-(ω-hydroxyalkoxy)-1α,25-dihydroxyvitamin D3 analogues, including 2-epi-ED-71 and their 20-epimers with HL-60 cell differentiation activity. J. Org. Chem.,2004,69, 7463-7471.
[87]Tsugawa, N.; Nakagawa, K.; Kurobe, M.; Ono, Y.; Kubodera, N.; Ozono, K. Okano, T. In vitro biological activities of a series of 2β-substituted analogues of 1α,25-dihydroxyvitamin D3. Biol. Pharm. Bull.,2000,23,66-71.
[88]Ono, Y.; Watanabe, H.; Shiraishi, A.; Takeda, S.; Higuchi, Y.; Sato, K.; Tsugawa, N.; Okano, T.; Kobayashi, T.; Kubodera, N. Synthetic studies of vitamin D analogs. XXIV. Synthesis of active vitamin D3 analogs substituted at the 2β-position and their preventive effects on bone mineral loss in ovariectomized rats. Chem. Pharm. Bull.,1997,45,1626-1630.
[89]Perlman K.L.; Swenson R.E.; Paaren H.E.; Schnoes H.K.; DeLuca H.F. Novel synthesis of 19-nor-vitamin D compounds. Tetrahedron Lett.,1991,32, 7663-7666.
[90]Bouillon R.; Sarandeses L.A.; Allewaert K.; Zhao J.; Mascarenas J.L.; Mourino A.; Vrielynck S.; DeClercq P.; Vandewalle M. Biologic activity of dihydroxylated 19-nor-(pre)vitamin D3. J. Bone. Miner. Res.,1993,8, 1009-1015.
[91]Sicinski, R.R.; Prahl, J.M.; Smith, C.M.; DeLuca, H.F. New 1α,25-dihydroxy-19-norvitamin D3 compounds of high biological activity: synthesis and biological evaluation of 2-hydroxymethyl,2-methyl and 2-methylene analogues. J. Med. Chem.,1998,41,4662-4674.
[92]Shevde, N.K.; Plum, L.A.; Clagett-Dame, M.; Yamamoto, H.; Pike, J.W.; DeLuca, H.F. A potent analog of 1α,25-dihydroxyvitamin D3 selectively induces bone formation. Proc. Natl. Acad. Sci.,2002,99,13487-13491.
[93]Sicinski R.R.; Rotkiewicz P.; Kolinski A.; Sicinska W.; Prahl J.M.; Smith C.M.; DeLuca H.F. 2-Ethyl and 2-ethylidene analogues of 1α,25-dihydroxy-19-norvitamin D3:synthesis, conformational analysis, biological activities, and docking to the modeled rVDR ligand binding domain. J. Med. Chem.,2002,45,3366-3380.
[94]Ono, K.; Yoshida, A.; Saito, N.; Fujishima, T.; Honzawa, S.; Suhara, Y.; Kishimoto, S.; Sugiura, T.; Waku, K.; Takayama, H.; Kittaka, A. Efficient synthesis of 2-modified 1α,25-dihydroxy-19-norvitamin D3 with julia olefination: high potency in induction of differentiation on HL-60 cells. J. Org. Chem.,2003, 68,7407-7415.
[95]Sicinski, R.R.; Perlman, K.L.; DeLuca, H.F. Synthesis and biological activity of 2-hydroxy and 2-alkoxy analogs of 1α,25-dihydroxy-19-norvitamin D3. J. Med. Chem.,1994,37,3730-3738.
[96]Kubodera N.; Okano T.; Nakagawa K.; Ozono K.; Mikami, K. Biological activities of 19-nor-1α,25-dihydroxyvitamin D3 analogs singly dehydroxylated at the C-1 or C-3 position of the A-ring. Curr. Pharm. Des.,2000,6,791-801.
[97]Olivera C.J.; Bula C.M.; Bishop J.E.; Adorini L.; Manchand P.; Uskokovic M.R.; Norman A.W. Characterization of five 19-nor-analogs of la,25(OH)2-vitamin D3 with 20-cyclopropyl-modified side-chains:implications for ligand binding and calcemic properties. J. Steroid. Biochem. Mol. Biol.,2004, 89-90,99-106.
[98]Wecksler W.R.; Norman A.W. Studies on the mode of action of calciferol. XXV. la,25-dihydroxy-5,6-trans-vitamin D3, the 5E-isomer of la,25-dihydroxyvitamin D3. Steroids,1980,35,419-425.
[99]Hisatake J.I.; Kubota T.; Hisatake Y.; Uskokovic M.; Tomoyasu S.; Koeffler, H.P.5,6-trans-16-ene-Vitamin D3:A new class of potent inhibitors of proliferation of prostate, breast, and myeloid leukemic cells. Cancer Res.,1999, 59,4023-4029.
[100]Fujishima, T.; Konno, K.; Nakagawa, K.; Tanaka, M.; Okano, T.; Kurihara, M.; Miyata, N.; Takayama, H. Synthesis and biological evaluation of all A-ring stereoisomers of 5,6-trans-2-methyl-1,25-dihydroxyvitamin D3 and their 20-epimers:possible binding modes of potent A-ring analogues to vitamin D receptor. Chem. Biol.,2001,8,1011-1024.
[101]Okamura W.H.; Aurrecoechea J.M.; Gibbs R.A.; Norman A.W. Synthesis and biological activity of 9,11-dehydrovitamin D3 analogues:stereoselective preparation of 6β-vitamin D vinylallenes and a concise enynol synthesis for preparing the A-ring. J. Org. Chem.,1989,54,4072-4083.
[102]Steinmeyer A.; Neef G.; Kirsch G.; Schwarz K.; Rach P.; Haberey M.; Thieroff-Ekerdt R. Synthesis and biological activities of 8(14)a-homo-calcitriol. Steroids,1992,57,447-452.
[103]Bouillon R.; Allewaert K.; Vanleeuwen J.P.T.M.; Tan B.K.; Xiang D.Z.; De Clercq P.; Vandewalle M.; Pols H.A.P.; Bos M.P.; Van Baelen H.; Birkenhager J.C. Structure function analysis of vitamin D analogs with C-ring modifications. J. Biol. Chem.,1992,267,3044-3051.
[104]Maynard D.F.; Norman A.W.; Okamura W.H.18-Substituted derivatives of vitamin D:18-acetoxy-1α,25-dihydroxyvitamin D3 and related analogues. J. Org. Chem.,1992,57,3124-3217.
[105]Nilsson K.; Valles M.J.; Castedo L.; Mourino A. Synthesis and biological evaluation of 18-substituted analogs of 1α,25-dihydroxyvitamin D3. Bioorg. Med. Chem. Lett.,1993,3,1855-1858.
[106]Jeganathan S.; Johnston A.D.; Kuenzel E.A.; Norman A.W.; Okamura W.H. Thermal rearrangement of vinylallenes:Synthesis of 3-deoxy-la-hydroxy-14-epi previtamin D3. J. Org. Chem.,1984,49, 2152-2158.
[107]Sicinski R.R.; Perlman K.L.; Prahl J.; Smith C.; DeLuca H.F. Synthesis and biological activity of 1α,25-dihydroxy-18-norvitamin D3 and 1α,25-dihydroxy-18,19-dinorvitamin D3. J. Med. Chem.,1996,39,4497-4506.
[108]Noboru K. A new look at the most successful prodrugs for active vitamin D (D hormone):alfacalcidol and doxercalciferol. Molecules,2009,14, 3869-3880.
[109]Voigts, A.L.; Felsenfeld, A.J.; Llach, F. The effects of calciferol and its metabolites on patients with chronic renal failure. I. Calciferol, dihydrotachysterol, and calcifediol. Arch. Inter. Med.,1983,143,960-963.
[110]Brancaccio, D.; Gallieni, M. Recent advances in intravenous calcitriol treatment. Curr. Opin. Neph. Hyper.,1994,3,411-416.
[111]Takahashi, H.; Ibe, M.; Kinouchi, M.; Yamamoto, A.I.; Hashimoto, Y.; Iizuka, H. Similarly potent action of 1,25-dihydroxyvitamin D3 and its analogues, tacalcital, calcipotriol, and maxacalcitol on normal human keratinocyte proliferation and differentiation. J. Dermatol. Sci.,2003,31,21-28.
[112]Noboru, K. Pharmaceutical studies on vitamin D derivatives and practical syntheses of six commercially available vitamin D derivatives that contribute to current clinical practice. Heterocycles,2010,80,83-98.
[113]Wu-Wong J.R.; Tian, J.; Goltzman, D. Vitamin D analogs as therapeutic agents: A clinical study update. Curr. Opin. Invest. Drugs,2004,5,320-326.
[114]Jones, G. Vitamin D Analogs. Endocrinol. Metab. Clin. N. Am.,2010,39, 447-472.
[115]Brown, A.J.; Slatopolsky, E. Vitamin D analogs:Therapeutic applications and mechanisms for selectivity. Mol. Aspects Med.,2008,29,433-452.
[116]Fumihiko, I; Shin, S. Maxacalcitol. Farumashia,2003,39,967-969.
[117]Ikuo, I. Maxacalcitol, a medicine for secondary hyperparathyroidism (2°HPT). Nippon Yakurigaku Zasshi,2003,121,65-72.
[118]Akinobu, K. OXAROL ointment:new topical drug to psoriasis, icthyosis, palmoplantar keratosis. Cell (Tokyo, Japan),2001,33,531-538.
[119]Barker, J. N. W. N.; Ashton, R. E.; Marks, R.; Harris, R. I.; Berth-Jones, J. Topical maxacalcitol for the treatment of psoriasis vulgaris:a placebo-controlled, double-blind, dose-finding study with active comparator. Brit. J. Dermatol.,1999,141,274-278.
[120]Shimizu H.; Shimizu K.; Kubodera N.; Mikami, T.; Tsuzaki, K.; Suwa, H.; Harada, K.; Hiraide, A.; Shimizu, M.; Koyama, K.; Ichikawa, Y.; Hirasawa, D.; Kito, Y.; Kobayashi, M.; Kigawa, M.; Kato, M.; Kozono, T.; Tanaka, H.; Tanabe, M.; Iguchi, M.; Yoshida, M. Industrial synthesis of maxacalcitol, the antihyperparathyroidism and antipsoriatic vitamin D3 analogue exhibiting low calcemic activity. Org. Pro. Res. Devel.,2005,9,278-287.
[121]Dodson, R.M.; Goldkamp, A.H.; Muir, R.D. J. Am. Chem. Soc.,1960,82, 4026-4033.
[122]Arturo P.M.; Paul A.G. Synthesis of the highly oxygenated ergostane type steroid (+)-withanolide E. J. Am. Chem. Soc.,1991,113,1057-1059.
[123]Matsuya, Y.; Yamakawa, Y.I.; Tohda, C.; Teshigawara, K.; Yamada, M.; Nemoto, H. Synthesis of sominone and its derivatives based on an RCM strategy:Discovery of a novel anti-Alzheimer's disease medicine candidate "denosomin". Org. Lett.,2009,11,3970-2973.
[124]Sheikh, S.E.; Greffen, A.M.; Lex, J.; Neudorfl, J.M.; Schmalz, H.G. Synthesis of the core structure of the cyclocitrinols via SmI2-mediated fragmentation of a cyclopropane precursor. Synlett.,2007,12,1881-1884.
[125]Kaneko, C.; Yamada, S.; Sugimoto, A.; Ishikawa, M.; Sasaki, S.; Suda, T. 1α-Hydroxylated of cholesterol and the related 3-hydroxysteroids. Tetrahedron Lett.,1973,26,2339-2342.
[126]Kaneko, C.; Sugimoto, A.; Yamada, S.; Ishikawa, M.; Sasaki, S.; Suda, T. Hydroboration of steroidal-1,5-dien-3β-ols:A general procedure for the introduction of a hydroxyl group at la-position of 3-oxygenerated steroids. Chem. Pharm. Bull.,1974,22,2101-2107.
[127]Shvo, Y.; Arisha, A.H.I. Regioselective catalytic dehydrogenation of aldehydes and ketones. J. Org. Chem.,1998,63,5640-5642.