Bioorganic and Medicinal Chemistry p. 8019 - 8032 (2013)
Update date:2022-08-15
Topics:
Tanpure, Rajendra P.
George, Clinton S.
Strecker, Tracy E.
Devkota, Laxman
Tidmore, Justin K.
Lin, Chen-Ming
Herdman, Christine A.
Macdonough, Matthew T.
Sriram, Madhavi
Chaplin, David J.
Trawick, Mary Lynn
Pinney, Kevin G.
Diversely functionalized, fused aryl-alkyl ring systems hold a prominent position as well-established molecular frameworks for a variety of anti-cancer agents. The benzosuberene (6,7 fused, also referred to as dihydro-5H-benzo[7] annulene and benzocycloheptene) ring system has emerged as a valuable molecular core component for the development of inhibitors of tubulin assembly, which function as antiproliferative anti-cancer agents and, in certain cases, as vascular disrupting agents (VDAs). Both a phenolic-based analogue (known as KGP18, compound 39) and its corresponding amine-based congener (referred to as KGP156, compound 45), which demonstrate strong inhibition of tubulin assembly (low micromolar range) and potent cytotoxicity (picomolar range for KGP18 and nanomolar range for KGP156) are noteworthy examples of such benzosuberene-based compounds. In order to extend the structure-activity relationship (SAR) knowledge base related to benzosuberene anti-cancer agents, a series of eleven analogues (including KGP18) were prepared in which the methoxylation pattern on the pendant aryl ring as well as functional group incorporation on the fused aryl ring were varied. The synthetic approach to these compounds featured a sequential Wittig olefination, reduction, Eaton's reagent-mediated cyclization strategy to achieve the core benzosuberone intermediate, and represented a higher-yielding synthesis of KGP18 (which we prepared previously through a ring-expansion strategy). Incorporation of a fluorine or chlorine atom at the 1-position of the fused aryl ring or replacement of one of the methoxy groups with hydrogen (on the pendant aryl ring of KGP18) led to benzosuberene analogues that were both strongly inhibitory against tubulin assembly (IC50 approximately 1.0 μM) and strongly cytotoxic against selected human cancer cell lines (for example, GI50 = 5.47 nM against NCI-H460 cells with fluoro-benzosuberene analogue 37). A water-soluble phosphate prodrug salt of KGP18 (referred to as KGP265, compound 44) and a water-soluble serinamide salt (compound 48) of KGP156 were also synthesized and evaluated in this study.
View Morewebsite:http://www.shochem.com
Contact:021-50800795
Address:No.1043, Halei Rd, Zhangjiang Hi-Tech Park, Shanghai, Postcode 201203, China
SHANGHAI ARCADIA BIOTECHNOLOGY LTD.
Contact:+86-21-61353236
Address:SUITE 901, BUILDING WENSLI, 1378 LU JIA BANG RD, SHANGAHI 200011, P.R.CHINA
Antaeus Bio-technology Co., LTD
Contact:021-31252569
Address:shanghai pudong
Lonzeal Pharmaceuticals Co., Ltd.
website:http://www.lonzeal.com
Contact:+86-13381011962
Address:RM 801, Yue MOMA, No. 26 Anningzhuang Rd. Haidian District, Beijing, China
Contact:+86 21 34123252
Address:14, 4580 Dushi, Shanghai, China
Doi:10.1007/BF00472518
(1991)Doi:10.1021/jo00030a051
(1992)Doi:10.1080/15533174.2011.613432
()Doi:10.1002/anie.201108037
(2012)Doi:10.1002/ange.202005183
(2020)Doi:10.1002/chem.201103924
(2012)