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. 2012 Jul 10;3(8):673-7.
doi: 10.1021/ml300143d. eCollection 2012 Aug 9.

Creation of readily accessible and orally active analogue of cortistatin a

Naoyuki Kotoku  1 , Yuji Sumii  1 , Takeshi Hayashi  1 , Satoru Tamura  1 , Takashi Kawachi  1 , Sho Shiomura  1 , Masayoshi Arai  1 , Motomasa Kobayashi  1
Affiliations

Creation of readily accessible and orally active analogue of cortistatin a

Naoyuki Kotoku et al. ACS Med Chem Lett. .

Abstract

Syntheses of structurally simplified analogues of cortistatin A (1), a novel antiangiogenic steroidal alkaloid from Indonesian marine sponge, and their biological activities were investigated. The analogues were designed by considering the 3-D structure of 1. Compound 30, in which the isoquinoline moiety was appended to the planar tetracyclic core structure, showed potent antiproliferative activity against human umbilical vein endothelial cells (HUVECs) together with high selectivity and also showed in vivo antiangiogenic activity and significant antitumor effect by oral administration.

Keywords: Cortistatin A; analogue synthesis; antiangiogenesis; marine sponge; structure−activity relationship.

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Figures

Figure 1
Figure 1
Chemical structure of cortistatins.
Figure 2
Figure 2
X-ray structure of cortistatin A (1).
Figure 3
Figure 3
Design of cortistatin analogues 12 and 13. The top and side views of the imposed 3D structures with cortistatin A (1) were also shown.
Scheme 1
Scheme 1. Synthesis of Analogue 12
Reagents and conditions: (a) DIBAL-H, CuI, t-BuMgCl, HMPA, THF, −78 °C, 77%; (b) ethylene glycol, (COOH)2·2H2O, CH3CN; (c) PhNTf2, KHMDS, THF, −78 °C, 78% (2 steps); (d) 20, Pd(PPh3)4, K2CO3, DMF, 50 °C; (e) p-TsOH, acetone/H2O, 52% (2 steps); (f) H2, Pd–C, AcOEt, 92%; (g) BrCH2PPh3Br, NaHMDS, THF, 86%; (h) 21, Pd(dppf)Cl2, Cs2CO3, AsPh3, DMF, 80 °C, 75%; (i) 5 N HCl, THF; (j) (HCHO)n, NaBH(OAc)3, CH2Cl2; HPLC separation, 30% (2 steps).
Scheme 2
Scheme 2. Synthesis of Analogue 23
Reagents and conditions: (a) NaH, THF, 18, 50 °C; HPLC separation, 23%.
Scheme 3
Scheme 3. Synthesis of Analogue 13
Reagents and conditions: (a) TMSCl, NaI, HMDS, CH3CN; (b) IBX, DMSO, 71% (2 steps); (c) PhNTf2, KHMDS, THF, −78 °C, 94%; (d) CO (gas), Pd(PPh3)4, MeOH, Et3N, DMF, 98%; (e) DIBAL-H, CH2Cl2, −78 °C; (f) Dess–Martin periodinane, NaHCO3, CH2Cl2, 67% (2 steps); (g) 1,3-cyclohexanedione, ethylenediamine, AcOEt, 97%.
Scheme 4
Scheme 4. Synthesis of Analogue 30
Reagents and conditions: (a) potassium azodicarboxylate, AcOH, 99%; (b) L-Selectride, THF, 80%; (c) Dess–Martin periodinane, NaHCO3, CH2Cl2; (d) 1,3-cyclohexanedione, ethylenediamine, AcOEt, 64% (2 steps).
Figure 4
Figure 4
In vivo antiangiogenic effect of analogue 30. (a) Mean ± SD hemoglobin content in the matrigel of each group; *: P < 0.05. (b) Images of Matrigel plugs after 10 days.
Figure 5
Figure 5
In vivo antitumor effect of analogue 30. (a) Mean ± SD tumor weight of each group; *: P < 0.05. (b) Images of isolated tumors after two weeks.
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