Design of drugs for Vitamin D receptor mutant related to hereditary vitamin D-resistant rickets

• Project/Area Number: 15590107
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: National Institute of Health Sciences
• Principal Investigator: KURIHARA Masaaki National Institute of Health Sciences, 有機科学部 (20205206)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000); Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
• Keywords: vitamin D_3 analogues / hereditary vitamin D-resistant rickets / vitamin D receptor / コンピュータモデリング

Research Abstract

Hereditary vitamin D-resistant rickets(HVDRR) is a genetic disorder caused by mutations in the vitamin D receptor, which lead to resistance to 1a,25-dihydroxyvitamin D_3[1a,25(OH)_2D_3]. We found that the A ring-modified analogues, 2a-(3-hydroxypropyl)- and 2a-(3-hydroxypropoxy)- 1a,25(OH)_2D_3, (O1C3 and O2C3) can bind better than the natural hormone to the mutant VDR (R274A), which similar to the HVDRR mutant, R274L, had lost the hydrogen bond to the 1a-hydroxyl group of 1a,25(OH)_2D_3,.

Research Products

• [Journal Article] Design and Synthesis of Cyclic Urea Compounds : A Pharmacological Study for Retinoidal Activity (2004)
  • Author(s): M.Kurihara, A.S.S.Rouf, H.Kansui, H.Kagechika H.Okuda, N.Miyata
  • Journal Title: Bioorg.Med.Chem.Lett. 14 Pages: 4131-4134
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] α-Amino Acid Side-Chain Chiral Centres Control the Helical Screw Sense of Peptides without a Chiral Centre at the α-Carbon (2004)
  • Author(s): M.Tanaka, Y.Demizu, M.Doi, M.Kurihara, H.Suemune
  • Journal Title: Angew.Chem.Int.Ed. 43 Pages: 5360-5363
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Design and Efficient Synthesis of 2α-(w-Hydroxyalkoxy)-1α, 25-dihydroxyvitamin D_3 An alogues, Including 2-epi-ED-71 and Their 20-Epimers with HL-60 Cell Differentiation Activity (2004)
  • Author(s): N.Saito, Y.Suhara, M.Kurihara, T.Fujishima, S.Honzawa, H.Takayanagi, T.Kozono, M.Matsumoto, M.Ohmori, N.Miyata, H.Takayama, A.Kittaka
  • Journal Title: J.Org.Chem. 69 Pages: 7463-7471
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Synthesis of C_<60> derivative for photoaffinity labeling (2004)
  • Author(s): E.Okada, Y.Komazawa, M.Kurihara, H.Inoue, N.Miyata, H.Okuda, T.Tsuchiya
  • Journal Title: Tetrahedron Lett. 45 Pages: 527-529
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 2,2-Functionlized Analogues of 1α, 25-Dihydroxyvitamin D_3, The Potent Inducers of Cell Differentiation (2004)
  • Author(s): T.Fujishima, A.Kittaka, M.Kurihara, N.Saito, S.Honzawa, S.Kishimoto, T.Sugiura, K.Waku, H.Takayama
  • Journal Title: J.Steroid Biochem.Mol.Biol. 89-90 Pages: 89-92
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Design and Synthesis of Cyclic Urea Compounds : A Pharmacological Study for Retinoidal Activity (2004)
  • Author(s): M.Kurihara, A.S.S.Rouf, H.Kansui, H.Kagechika, H.Okuda, N.Miyata
  • Journal Title: Bioorg.Med.Chem.Lett. 14 Pages: 4131-4134
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Chiral Centers in the Side Chains of α-Amino Acids Control the Helical Screw Sense of Peptides (2004)
  • Author(s): M.Tanaka, Y.Demizu, M.Doi, M.Kurihara, H.Suemune
  • Journal Title: Angew.Chem.Int.Ed. 43 Pages: 5360-5363
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Design and Efficient Synthesis of 2α-(w-Hydroxyalkoxy)-1α,25-dihydroxyvitamin D_3 Analogues, Including 2-epi-ED-71 and Their 20-Epimers with HL-60 Cell Differentiation Activity (2004)
  • Author(s): N.Saito, Y.Suhara, M.Kurihara, T.Fujishima, S.Honzawa, H.Takayanagi, T.Kozono, M.Matsumoto, M.Ohmori, N.Miyata, H.Takayama, A.Kittaka
  • Journal Title: J.Org.Chem. 69 Pages: 7463-7471
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Synthesis of C_<60> derivative for photoaffinity labeling (2004)
  • Author(s): E.Okada, Y.Komazawa, M.Kurihara, H.Inoue, N.Miyata, H.Okuda, T.Tsuchiya, Y.Yamakoshi
  • Journal Title: Tetrahedron Lett. 45 Pages: 527-529
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 2,2-Functionlized Analogues of 1α,25-Dihydroxyvitamin D_3, The Potent Inducers of Cell Differentiation (2004)
  • Author(s): T.Fujishima, A.Kittaka, M.Kurihara, N.Saito, S.Honzawa, S.Kishimoto, T.Sugiura, K.Waku, H.Takayama
  • Journal Title: J.Steroid Biochem.Mol.Biol. 89-90 Pages: 89-92
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prediction of helical screw sense of oligopeptides containing chiral amino acids : computational study (2004)
  • Author(s): M.Kurihara, Y.Sato, S.Nomoto, H.Okuda, M.Oba, Y.Demizu, M.Tanaka, H.Suemune
  • Journal Title: Peptide Science 2003 Pages: 411-412
  • NAID: 10012654502
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Design and Efficient Synthesis of 2α-(w-Hydroxyalkoxy)-lα,25-dihydroxyvitamin D_3 Analogues, Including 2-epi-ED-71 and Their 20-Epimers with HL-60 Cell Differentiation (2004)
  • Author(s): N.Saito, Y.Suhara, M.Kurihara, T.Fujishima, S.Honzawa, H.Takayanagi, T.Kozono, M.Matsumoto
  • Journal Title: J.Org.Chem. 69 Pages: 7463-7471
• [Journal Article] Synthesis of C_<60> derivative for photoaffinity labeling (2004)
  • Author(s): E.Okada, Y.Komazawa, M.Kurihara, H.Inoue, N.Miyata, H.Okuda, T.Tsuchiya.
  • Journal Title: Tetrahedron Lett. 45 Pages: 527-529
• [Journal Article] 2,2-Functionlized Analogues of 1α, 25-Dihydroxyvitamin D_3, The Potent Inducers of Cell Differentiation (2004)
  • Author(s): T.Fujishima, A.kittaka, M.Kurihara, N.Saito, S.Honzawa, S
  • Journal Title: J.Steroid Biochem.Mol.Biol. 89-90 Pages: 89-92
• [Journal Article] 2α-(3-Hydroxypropyl)- and 2α-(3-Hydroxypropoxy)-1α, 25-vitamin D_3 Accessible to vitamin D Receptor Mutant Related to Hereditary Vitamin D-Resistant Rickets (2003)
  • Author(s): A.Kittaka, M.Kuribara, S.Peleg, Y.Suhara, H.Takayama
  • Journal Title: Chem.Pharm.Bull. 51 Pages: 357-358
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 2α-(3-Hydroxypropyl)- and 2α-(3-Hydroxypropoxy)- 1α,25-vitamin D_3 Accessible to Vitamin D Receptor Mutant Related to Hereditary Vitamin D-Resistant Rickets (2003)
  • Author(s): A.Kittaka, M.Kurihara, S.Peleg, Y.Suhara, H.Takayama
  • Journal Title: Chem.Pharm.Bull. 51 Pages: 357-358
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Convenient Preparation of Cyclic Acetals Using Diols, TMS-source and a Catalytic Amount of TMSOTf (2003)
  • Author(s): M.Kurihara, W.Hakamata
  • Journal Title: J.Org.Chem. 68 Pages: 3413-3415
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] An Extended Planar C_5 Conformation and a 3_<10>-Helical Structure of Peptide-Foldamer Constituted of Diverse a-Ethylated α,α-Disubstituted α-Amino Acids (2003)
  • Author(s): M.Tanaka, S.Nishimura, M.Oba, Y.Demizu, M.Kurihara, H.Suemune
  • Journal Title: Chemistry Eur.J. 9 Pages: 3082-3090
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Concise Synthesis and Biological Activities of 2α-Alkyl- and 2α-(ω-Hydroxyalkyl)-20-epi-1α,25-dihydroxyvitamin D_3 (2003)
  • Author(s): S.Honzawa, Y.Suhara, K.Nihei, N.Saito, S.Kishimoto, T.Fujishima, M.Kurihara, T.Sugiura, K.Waku, H.Takayama, A.Kittaka
  • Journal Title: Bioorg.Med.Chem.Lett. 13 Pages: 3503-3506
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Computational Study on Conformation of Oligopeptides Containing Chiral alpha, alpha-Disubstituted Amino Acids (2003)
  • Author(s): M.Kurihara, M.Tanaka, M.Oba, H.Suemune
  • Journal Title: Peptides 2002 Pages: 786-787
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prediction of the helical screw sense of oligopeptides containing chiral alpha, alpha-disubstituted amino acids (2003)
  • Author(s): M.Kurihara, Y.Sato, M.Tanaka, M.Oba, Y.Demizu, H.Suemune, H.Okuda
  • Journal Title: Peptide Science 2002 Pages: 323-324
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 2α-(3-Hydroxypropyl)- and 2α-(3-Hydroxypropoxy)-1α,25-vitamin D_3 Accessible to Vitamin D Receptor Mutant Related to Hereditary Vitamin D-Resistant Rickets (2003)
  • Author(s): A.Kittaka, M.Kurihara, S.Peleg, Y.Suhara, H.Takayama
  • Journal Title: Chem.Pharm.Bull. 51 Pages: 357-358
• [Publications] M.Kurihara, W.Hakamata: "Convenient Preparation of Cyclic Acetals Using Diols, TMS-source and a Catalytic Amount of TMSOTf"J.Org.Chem.. 68. 3413-3415 (2003)
• [Publications] M.Tanaka, S.Nishimura, M.Oba, Y.Demizu, M.Kurihara, H.Suemune.: "An Extended Planar C_5 Conformation and a 3_<10>-Helical Structure of Peptide-Foldamer Constituted of Diverse α-Ethylated α,α-Disubstituted α-Amino Acids"Chemistry Eur.J.. 9. 3082-3090 (2003)
• [Publications] A.Kittaka, M.Kurihara, S.Peleg, Y.Suhara, H.Takayama: "2α-(3-Hydroxypropyl)- and 2α-(3-Hydroxypropoxy)-1α,25-vitamin D_3 Accessible to Vitamin D Receptor Mutant Related to Hereditary Vitamin D-Resistant Rickets"Chem.Pharm.Bull.. 51. 357-358 (2003)
• [Publications] S.Honzawa, Y.Suhara, K.Nihei, N.Saito, S.Kishimoto, T.Fujishima, M.Kurihara, T.Sugiura, K.Waku, H.Takayama, A.Kittaka.: "Concise Synthesis and Biological Activities of 2α-Alkyl-and 2a-(w-Hydroxyalkyl)-20-epi-1a,25-dihydroxyvitamin D_3"Bioorg.Med.Chem.Lett.. 13. 3503-3506 (2003)
• [Publications] M.Kurihara, M.Tanaka, M.Oba, H.Suemune: "Computational Study on Conformation of Oligopeptides Containing Chiral alpha, alpha-Disubstituted Amino Acids"Peptides 2002,. 786-787 (2003)
• [Publications] E.Okada, Y.Komazawa, M.Kurihara, H.Inoue, N.Miyata, H.Okuda, T.Tsuchiya, Y.Yamakoshi: "Synthesis of C_<60> derivative for photoaffinity labeling"Tetrahedron Lett.. 45. 527-529 (2004)