研究概要

天然物からの創薬を目指し, 新しい機能性天然分子の発見と創製を主テーマに研究を進めている. すなわち, 薬用資源植物を対象とした創薬シード分子の探索とともに, 天然から与えられたユニークな化学構造あるいは生物活性を持つ分子を, 合成化学, 医薬化学研究の素材として活用する有機化学Orientedな天然物化学研究を行っている. 具体的には以下の三つのテーマに取り組んでいる.

１）薬用資源植物からの新しい活性分子種（創薬シード分子）の追求 [単離, 精密構造解析, 構造変換など]

研究対象の一つとしてアカネ科のMitragyna属, Ophiorrhiza属, Adina属植物等が挙げられる. この中で, タイ・マレーシアでアヘン代用薬として用いられてきたMitragyna speciosaから強力な鎮痛活性を持つインドールアルカロイドを発見し, さらに天然分子の化学修飾により, バイオアベイラビリティーに優れたモルヒネをしのぐオピオイド受容体作動薬を創出することができた. その他, マチン科Gelsemium属植物含有アルカロイドをシード分子とした新規抗腫瘍薬開発のための研究を継続している. また, アルツハイマー病治療薬の開発を目指し, Chimonanthus 属, Lycopodium属, ヒガンバナ科植物のアルカロイドに関する化学的研究を行っている. キョウチクトウ科Voacanga africanaに含有されるイボガ型アルカロイドが痛み等に関与するTRPチャネルアンタゴニストであることを見出した. その他, キク科やムラサキ科などに含まれ天然毒素として知られるピロリジジンアルカロイドや, Kopsia属, Pandanus属, Heimia属, Catharanthus属, Ervatamia属植物などに含有される含窒素化合物に関する研究も行っている. 海外固有の植物についての研究は産生国研究者との共同研究として進めている.

M. Kitajima, Y. Yamaguchi, T. Yanagisawa, N. Kogure, J. Ogata, R. Kikura-Hanajiri, and H. Takayama:
Biphenyl quinolizidine lactone alkaloids from "sinicuichi" (Heimia salicifolia).
Tetrahedron,75(27), 3733-3739 (2019).

 

M. Kitajima, K. Okabe, M. Yoshida, R. Nakabayashi, K, Saito, N. Kogure, and H. Takayama:
New Otonecine-type Pyrrolizidine Alkaloid from Petasites japonicus.
J. Nat. Med.,73(3), 602-607 (2019).

 

M. Kitajima, S. Nakano, N. Kogure, S. Subhadhirasakul, and H. Takayama:
New Indole Alkaloids from Ervatamia cumingiana.
Heterocycles,99(1), 213-221 (2019).

 

M. Kitajima, T. Yanagisawa, M. Tsukahara, Y. Yamaguchi, N. Kogure, R. Kikura-Hanajiri, Y. Goda, O. Iida, Y. Sugimura, N. Kawahara, and H. Takayama:
Biphenyl Ether and Biphenyl Quinolizidine Lactone Alkaloids from Heimia salicifolia.
Tetrahedron,74(4), 441-452 (2018).

 

T. Onozawa, M. Kitajima, N. Kogure, N. Peerakam, D. Santiarworn, and H. Takayama:
A Cyclopeptide and a Tetrahydroisoquinoline Alkaloid from Ophiorrhiza nutans.
J. Nat. Prod.,80(7), 2156-2160 (2017).

 

N. Kogure, M. Maruyama, S. Wongseripipatana, M. Kitajima, and H. Takayama:
New Lycopodine-type Alkaloids from Lycopodium carinatum.
Chem. Pharm. Bull.,64(7), 793-799 (2016).

 

M. Kitajima, M. Nakazawa, Y. Wu, N. Kogure, R. Zhang, and H. Takayama:
Kopsiyunnanines L and M, Strychnos-related Monoterpenoid Indole Alkaloids from Yunnan Kopsiaarborea.
Tetrahedron,72(42), 6692-6696 (2016).

M. Kitajima, T. Koyama, Y. Wu, N. Kogure, R. Zhang, and H. Takayama:
Kopsiyunnanines J1 and J2, New Strychnos-type Homo-Monoterpenoid Indole Alkaloids from Kopsiaarborea.
Nat. Prod. Commun.,10(1), 49-51 (2015).

M. Kitajima, M. Iwai, N. Kogure, R. Kikura-Hanajiri, Y. Goda, and H. Takayama :
Aspidosperma-aspidosperma-type Bisindole Alkaloids from Voacanga africana.
Tetrahedron,69(2) , 796-801 (2013).

 

M. Kitajima, S. Ohara, N. Kogure, D. Santiarworn, and H. Takayama:
β-Carboline-type indole alkaloid glycosides from Ophiorrhiza trichocarpon.
Tetrahedron,69(45) , 9451-9456 (2013).

 

M. Kitajima, S. Ohara, N. Kogure, Y. Wu, R. Zhang, and H. Takayama :
New Indole Alkaloids from Melodinus henryi.
Heterocycles,85(8), 1949-1959 (2012).

 

N. Kogure, Y. Suzuki, Y. Wu, M. Kitajima, R. Zhang, and H. Takayama :
Chemical Conversion of Strychnine into Kopsiyunnanine-I, a New Hexacyclic Indole Alkaloid from Yunnan Kopsia arborea.
Tetrahedron Lett.,53(48), 6523-6526 (2012).

 

K. Katakawa, H. Mito, N. Kogure, M. Kitajima, S. Wongseripipatana, M. Arisawa, and H. Takayama :
Ten New Fawcettimine-related Alkaloids from Three Species of Lycopodium.
Tetrahedron,67(35) 6561-6567 (2011).

 

M. Kitajima, A. Tanaka, N. Kogure, and H. Takayama :
Metacolchicine, A New Colchicinoid from Sandersonia aurantiaca.
Heterocycles,83,1903-1907 (2011).

 

Y. Yamada, M. Kitajima, S. Wongseripipatana, N. Kogure, and H. Takayama :
Seven New Monoterpenoid Indole Alkaloids from Gelsemium elegans.
Chem. Asian J.,6(1), 166-173 (2011).

 

Y. Wu, M. Kitajima, N. Kogure, Y. Wang, R. Zhang, and H. Takayama :
Two New Aspidosperma Indole Alkaloids from Yunnan Kopsia arborea.
Chem. Pharm. Bull.,58(7), 961-963 (2010).

M. A. Tan, M. Kitajima, N. Kogure, M. G. Nonato, and H. Takayama :
New Pyrrolidine Alkaloids from the Roots of Pandanus amaryllifolius.
Tetrahedron Lett.,51(31), 4143-4146 (2010).

 

M. Kitajima, H. Kobayashi, N. Kogure, and H. Takayama :
New Oxindole and Indole Alkaloids from Gelsemium rankinii.
Tetrahedron,66(32), 5987-5992 (2010).

M. A. Tan, M. Kitajima, N. Kogure, M. G. Nonato, and H. Takayama :
Isolation of Pandamarilactonine-H from the Roots of Pandanus amaryllifolius and Synthesis of epi-Pandamarilactonine-H.
J. Nat. Prod.,73(8), 1453-1455 (2010).

 

Hasnah M. Sirat, Deny Susanti, Farediah Ahmad, H. Takayama, and M. Kitajima :
Amide, Triterpene and Flavonoids from the Leaves of Malastoma malabathricum L.
J. Nat. Med.,64(4), 492-495 (2010).

Y. Yamada, M. Kitajima, N. Kogure, S. Wongseripipatana, and H. Takayama :
Spectroscopic Analyses and Chemical Transformation for
Structure Elucidation of Two Novel Indole Alkaloids from
Gelsemium elegans.
Tetrahedron Lett.,50(26), 3341-3344 (2009).

 



２） 有用生物活性天然物（生体機能性分子）に関する合成化学研究 [不斉全合成, 化学変換, 効率的供給法の開発など]

上記の研究１）にて見いだした有用天然アルカロイドを効率的に合成する研究を行っている. 最近の研究テーマは, Lycopodium属, Kopsia属, Voacanga属, Gelsemium属, Hunteria属, Gardneria属, Heimia属, Pandanus属, Aspidosperma属, Chimonanthus属, Lycoris属アルカロイド類やピロリジジンアルカロイド類の不斉全合成研究などであり, 複雑な化学構造を有する多くのアルカロイド類の初の不斉全合成を達成した.

K. Sato, N. Kogure, M. Kitajima, and H. Takayama:
Total Syntheses of Pleiocarpamine, Normavacurine, and C-Mavacurine.
Org. Lett.,21(9), 3342-3345 (2019).

 

H. Kaneko, S. Takahashi, N. Kogure, M. Kitajima, and H. Takayama:
Asymmetric Total Synthesis of Fawcettimine-Type Lycopodium Alkaloid, Lycopoclavamine-A.
J. Org. Chem.,84(9), 5645-5654 (2019).

 

K. Wada, N. Kogure, M. Kitajima, and H. Takayama:
Concise Asymmetric Total Synthesis of Lycopodine and Flabelliformine via Cascade Cyclization Reaction.
Tetrahedron Lett.,60(2), 187-190 (2019).

K. Sato, N. Takanashi, N. Kogure, M. Kitajima, and H. Takayama:
Formal Total Synthesis of (±)-Strictamine.
Heterocycles,97(1), 365-382 (2018).

T. Onozawa, M. Kitajima, N. Kogure, and H. Takayama:
Asymmetric Total Synthesis and Evaluation of Antitumor Activity of Ophiorrhisine A and Its Derivatives.
J. Org. Chem.,83(24), 15312-15322 (2018).

 

T. Hirama, T. Umemura, N. Kogure, M. Kitajima, and H. Takayama:
Synthetic Study of Biphenylquinolizidine Alkaloids I. Asymmetric Total Synthesis of Lasubine I Featuring Organocatalyzed Asymmetric Intramolecular aza-Michael Addition.
Tetrahedron Lett.,58(3), 223-226 (2017).

 

S. Tooriyama, Y. Mimori, Y. Wu, N. Kogure, M. Kitajima, and H. Takayama:
Asymmetric Total Synthesis of Pentacyclic Indole Alkaloid Andranginine and Absolute Configuration of Natural Product Isolated from Kopsia arborea.
Org. Lett.,19(10), 2722-2725 (2017).

 

M. Kitajima, K. Watanabe, H. Maeda, N. Kogure, and H. Takayama:
Asymmetric Total Synthesis of Sarpagine-Related Indole Alkaloids Hydroxygardnerine, Hydroxygardnutine, Gardnerine, (E)-16-epi-Normacusine B, and Koumine.
Org. Lett.,18(8), 1912-1915 (2016).

 

R. Tokuda, Y. Okamoto, T. Koyama, N. Kogure, M. Kitajima, and H. Takayama:
Asymmetric Total Synthesis of Kopsiyunnanine K, a Monoterpenoid Indole Alkaloid with a Rearranged Skeleton.
Org. Lett.,18(14), 3490-3493 (2016).

 

N. Takanashi, K. Suzuki, M. Kitajima, and H. Takayama:
Total Synthesis of Conolidine and Apparicine.
Tetrahedron Lett.,57(3), 375-378 (2016).

H. Ishida, S. Kimura, N. Kogure, M. Kitajima, and H. Takayama:
Total Synthesis of (±)-Lycoposerramine-R, a Novel Skeletal Type of Lycopodium Alkaloid.
Tetrahedron,71(1), 51-56 (2015).

H. Ishida, S. Kimura, N. Kogure, M. Kitajima, and H. Takayama:
The First Asymmetric Total Synthesis of Lycoposerramine-R.
Org. Biomol. Chem.,13(28), 7762-7771 (2015).

M. Azuma, T. Yoshikawa, N. Kogure, M. Kitajima, and H. Takayama:
Biogenetically Inspired Total Syntheses of Lycopodium Alkaloids, (+)-Flabellidine and (–)-Lycodine.
J. Am. Chem. Soc.,136(33), 11618-11621 (2014).

M. Kitajima, Y. Murakami, N. Takahashi, Y. Wu, N. Kogure, R. Zhang, and H. Takayama:
Asymmetric Total Synthesis of Novel Pentacyclic Indole Alkaloid, Kopsiyunnanine E, Isolated from Kopsia arborea.
Org. Lett.,16(19), 5000-5003 (2014).

A. Nakayama, M. Kitajima, and H. Takayama :
Syntheses of Fawcettimine-type Lycopodium Alkaloids Utilizing Pauson-Khand Reaction.
Synlett,23(14), 2014-2024 (2012) Invited Account.

M. Harada, K. Asaba, M. Iwai, N. Kogure, M. Kitajima and H. Takayama :
Asymmetric Total Synthesis of an Iboga-Type Indole Alkaloid, Voacangalactone, Newly Isolated from Voacanga africana.
Org. Lett.,14(22), 5800-5803 (2012).

M. Kitajima and H. Takayama :
Lycopodium Alkaloids: Isolation and Asymmetric Synthesis.
Topics in Current Chemistry, “Alkaloid Synthesis”, ed. by H.-J. Knölker, Springer, 309, 1-32 (2012).

A. Nakayama, N. Kogure, M. Kitajima, and H. Takayama :
Asymmetric Total Synthesis of a Pentacyclic Lycopodium Alkaloid, Huperzine-Q.
Angew. Chem., Int. Ed.,50(35). 8025-8028 (2011).

K. Foo, T. Newhouse, I. Mori, H. Takayama, and P. S. Baran :
Total Synthesis Guided Structure Elucidation of (+)-Psychotetramine.
Angew. Chem., Int. Ed.,50(12), 2716-2719 (2011).

N. Takahashi, T. Ito, Y. Matsuda, N. Kogure, M. Kitajima, and H. Takayama :
Determination of Absolute Configuration of Trimeric Indole Alkaloid, Psychotrimine, by First Asymmetric Total Synthesis.
Chem. Commun.,46(14), 2501-2503 (2010).

M. A. Tan, M. Kitajima, N. Kogure, M. G. Nonato, and H. Takayama :
Isolation and Total Syntheses of Two New Alkaloids, Dubiusamines-A and-B, from Pandanus dubius.
Tetrahedron,66(18), 3353-3359 (2010).

A. Nakayama, N. Kogure, M. Kitajima, and H. Takayama :
First Asymmetric Total Syntheses of Fawcettimine-Type Lycopodium Alkaloids, Lycoposerramine-C and Phlegmariurine-A.
Org. Lett.,11(23), 5554-5557 (2009).

Y. Nishikawa, M. Kitajima, N. Kogure, and H. Takayama :
A Divergent Approach for the Total Syntheses of Cernuane-type and Quinolizidine-type Lycopodium Alkaloids.
Tetrahedron,65(8), 1608-1617 (2009).

T. Tanaka, N. Kogure, M. Kitajima, and H. Takayama :
Asymmetric Total Syntheses of Cyclic-Nitrone-Containing Phlegmarine-Type Lycopodium Alkaloids, Lycoposerramines-X and -Z.
J. Org. Chem.,74(22), 8675-8680 (2009).


３）天然物・合成品化合物ライブラリーを活用した創薬化学研究, 生物活性作用発現機序の解明研究

上記の研究で得られた天然分子及び合成化合物類については学内外の共同研究者により生物活性評価が実施され, その結果はこれら分子を基盤とした医薬化学研究へとフィードバックされている. これに関連する主な研究テーマとして, オピオイド性鎮痛アルカロイド, 抗腫瘍性ゲルセミウムアルカロイド・コプシアアルカロイド・コルヒチン誘導体, 脳機能に関与するリコポジウム属, ボアカンガ属及びヒガンバナ科アルカロイド, TRPチャネル・カンナビノイドCB1受容体アンタゴニスト活性を有するイボガ型アルカロイドなどに関する創薬化学研究を進めている.

M. Kitajima, A. Morita, S. Endo, N. Kogure, K. Higashi, K. Moribe, and H. Takayama:
Design and Synthesis of 4-Chlorocolchicine-Derived Prodrug Capable of Forming Nanoparticles by Self-assembly.
Heterocycles,95(1), 181-186 (2017).

K. Matsumoto, M. Narita, N. Muramatsu, T. Nakayama, K. Misawa, M. Kitajima, K. Tashima, T. Suzuki, H. Takayama, and S. Horie:
The Orally Active Opioid μ/δ Dual Agonist MGM-16, a Derivative of Indole Alkaloid Mitragynine, Exhibits Potent Analgesic Effect on Neuropathic Pain in Mice.
J. Pharmacol. Exp. Ther.,348(3), 383-392 (2014).

Y. Terada, S. Horie, H. Takayama, K. Uchida, M. Tominaga, and T. Watanabe:
Activation and Inhibition of Thermosensitive TRP Channels by Voacangine, an Alkaloid Present in Voacanga Africana, an African Tree.
J. Nat. Prod.,77(2), 285-297 (2014).

H. Nishiyama, M. Ono, T. Sugimoto, T. Sasai, N. Asakawa, S. Ueno, Y. Tominaga, T. Yaegashi, M. Nagaoka, T. Matsuzaki, N. Kogure, M. Kitajima, and H. Takayama:
4-Chlorocolchicine Derivatives Bearing a Thiourea Side Chain at the C-7 Position as Potent Anticancer Agents.
Med. Chem. Commun.,5(4), 452-458 (2014).

Y. Terada, M. Kitajima, F. Taguchi, H. Takayama, S. Horie, and T. Watanabe:
Identification of Indole Alkaloid Structural Units Important for Stimulus-Selective TRPM8 Inhibition: SAR Study of Naturally Occurring Iboga Derivatives.
J. Nat. Prod.,77(8), 1831-1838 (2014).

H. Nishiyama, M. Ono, T. Sugimoto, T. Sasai, N. Asakawa, T. Matsumoto, T. Yaegashi, M. Nagaoka, T. Matsuzaki, N. Kogure, M. Kitajima, and H. Takayama :
Synthesis and Biological Evaluation of 4-Chlorocolchicine Derivatives as Potent Anticancer Agents with Broad Effective Dosage Ranges.
Med. Chem. Comm.,3(12), 1500-1504 (2012).

N. Yasobu, M. Kitajima, N. Kogure, Y. Shishido, T. Matsuzaki, M. Nagaoka, and H. Takayama : Design, Synthesis, and Anti-tumor Activity of 4-Halocolchicines and their Pro-drugs Activated by Cathepsin B.
ACS Med. Chem. Lett.,2(5), 348-352 (2011).

M. Kitajima, M. Iwai, R. Kikura-Hanajiri, Y. Goda, M. Iida, H. Yabushita, and H. Takayama : Discovery of Indole Alkaloids with Cannabinoid CB1 Receptor Antagonistic Activity.
Bioorg. Med. Chem. Lett.,21, 1962-1964 (2011).

M. Lo, K. Matsumoto, M. Iwai, K. Tashima, M. Kitajima, S. Horie, and H. Takayama :
Inhibitory Effect of Iboga-type Indole Alkaloids on Capsaicin-induced Contraction in Isolated Mouse Rectum.
J. Nat. Med.,65(1), 157-165 (2011).

H. Takayama, Y. Yaegashi, M. Kitajima, X. Hanb, K. Nishimura, S. Okuyama and K. Igarashi :
Design, synthesis, and biological evaluation of tricyclic heterocycle-tetraamine conjugates as potent NMDA channel blockers.
Bioorg. Med. Chem. Lett.,17(17), 4729-4732 (2007).

H. Takayama, K. Misawa, N. Okada, H. Ishikawa, M. Kitajima, Y. Hatori, T. Murayama,
S. Wongseripipatana, K. Tashima, K. Matsumoto, and S. Horie :
New Procedure to Mask the 2,3-π Bond of the Indole Nucleus
and Its Application to the Preparation of Potent Opioid
Recepter Agonists with a Corynanthe Skeleton.
Org. Lett.,8(25), 5705-5708 (2006).