- Discovery of the cancer cell selective dual acting anti-cancer agent (Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile (A131)
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Selective targeting of cancer cells over normal cells is a key objective of targeted therapy. However few approaches achieve true mechanistic selectivity resulting in debilitating side effects and dose limitation. In this work we describe the discovery of A131 (4a), a new agent with an unprecedented dual mechanism of action targeting both mitosis and autophagy. Compound 4a was first identified in a phenotypic screen in which HeLa cells treated with 4a manifested mitotic arrest along with formation of multiple vesicles. Further investigations showed that 4a causes an increase in mitotic marker pH3 and autophagy marker LC3. Importantly 4a induces cell death in cancer cells while sparing normal cells which regrow after 4a is removed. Dual activities against pH3 and LC3 markers are required for cancer cell selectivity. An extensive SAR investigation confirmed 4a as the optimal dual inhibitor with potency against a panel of 30 cancer cell lines (average antiproliferative GI50 1.5 μM). In a mouse model of paclitaxel-resistant colon cancer, 4a showed 74% tumor growth inhibition when administered at a dose of 20 mg/kg IP twice a day.
- See, Cheng Shang,Kitagawa, Mayumi,Liao, Pei-Ju,Lee, Kyung Hee,Wong, Jasmine,Lee, Sang Hyun,Dymock, Brian W.
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p. 344 - 367
(2018/07/25)
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- Use of derivatives of indoles for the treatment of cancer
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The present invention relates to the use of derivatives of indoles having a general formula (I) as follow: for the manufacture of a pharmaceutical composition intended for the treatment of cancer.
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Page/Page column 52; 53
(2016/01/09)
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- SMALL MOLECULE INHIBITORS OF ISOPRENYLCYSTEINE CARBOXYL METHYLTRANSFERASE WITH POTENTIAL ANTICANCER ACTIVITY
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The present invention generally relates to inhibitors of isoprenylcysteine carboxyl methyltransferase (Icmt), in particularly to compounds that inhibit Icmt activity and pharmaceutical compositions thereof. The invention also relates to methods of disease treatment using the same.
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Page/Page column 58-59
(2011/02/24)
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- Glucocorticoid Mimetics, Methods of Making Them, Pharmaceutical Compositions and Uses Thereof
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Compounds of Formula (I) wherein R1, R2, R3, R4, R5, R6, and R7 are as defined herein, or a tautomer, prodrug, solvate, or salt thereof; pharmaceutical compositions containing such compounds, and methods of modulating the glucocorticoid receptor function and methods of treating disease-states or conditions mediated by the glucocorticoid receptor function or characterized by inflammatory, allergic, or proliferative processes in a patient using these compounds.
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Page/Page column 40-41
(2010/12/29)
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- Use of derivatives of indoles for the treatment of cancer
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The present invention relates to the use of derivatives of indoles having a general formula (I) as follow: for the manufacture of a pharmaceutical composition intended for the treatment of cancer.
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- Amino derivatives of indole as potent inhibitors of isoprenylcysteine carboxyl methyltransferase
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The enzyme isoprenylcysteine carboxyl methyltransferase (Icmt) plays an important role in the post-translational modification of proteins that are involved in the regulation of cell growth. The indole acetamide cysmethynil is by far the most potent and widely investigated Icmt inhibitor, but it has modest antiproliferative activity and may have pharmacokinetic limitations due to its lipophilic character. We report here that cysmethynil can be structurally modified to give analogues that are as potent in inhibiting Icmt but with significantly greater antiproliferative activity. Key modifications were the replacement of the acetamide side chain by tertiary amino groups, the n-octyl side chain by isoprenyl and the 5-m-tolyl ring by fluorine. Moreover, these analogues have lower lipophilicities that could lead to improved pharmacokinetic profiles.
- Go, Mei-Lin,Leow, Jo Lene,Gorla, Suresh Kumar,Schüller, Andreas Peter,Wang, Mei,Casey, Patrick J.
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experimental part
p. 6838 - 6850
(2010/11/18)
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- Synthesis of 3-Amino-2-(3-indolyl)propanol and propanoate derivatives and preliminary cardiovascular evaluation in rats
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A series of tryptamine analogues has been prepared and tested for their 5-HT1 receptor agonist properties. The incorporation of an alkoxy group at the C-5 position of the indole nucleus resulted in a short-lived and dose-dependent immediate ant
- Perez-Alvarez, Victor,Morales-Rios, Martha S.,Hong, Enrique,Joseph-Nathan, Pedro
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p. 246 - 252
(2007/10/03)
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- Process for the preparation of 3-amino-2-(5-fluoro and 5-methoxy-1H-indol-3-yl)propanoic acid derivatives
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The compounds having Formula I, STR1 wherein X is a fluorine or methoxy group, and R is a hydrogen or methyl group, such that R is hydrogen only when X is fluorine are novel. The compounds having Formula I and their acid addition salts are useful for the treatment of hypertension. Processes for the preparation of the compounds having Formula I and useful intermediates are described.
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- 3-Amino or amido-2-(1H-indol-3-yl) propanoic acid derivatives
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Disclosed are compounds characterized by the structural formula: STR1 Various compounds circumscribed by the foregoing formula in which: R is H, CH3 or CH2 CH3, R' is H, or STR2 X is H, F or OCH3, Y is H or Cl, and Z is H or STR3 are therapeutically useful as anti-hypertensive agents.
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