Synthesis, structure and anticancer activity of new geldanamycin amine analogs containing C(17)- or C(20)- flexible and rigid arms as well as closed or open ansa-bridges.
Eur J Med Chem
; 202: 112624, 2020 Sep 15.
Article
em En
| MEDLINE
| ID: mdl-32663707
ABSTRACT
The nucleophilic attack of amines at C(17) or C(17)/C(20) positions of geldanamycin's (GDM) benzoquinone, via initial 1,4-Michael conjugate addition mechanism, yield new analogs with closed or open ansa-bridges (1-31), respectively. X-ray structures of analogs 22 and 24 reveals an unexpected arrangement of the ansa-bridge in solid (conformer B), that is located between those of conformers A, prevailing in solution (trans-lactam), and C, crucial at binding to Hsp90 (cis-lactam). The structure of a new-type conformer B allows to better understand the molecular recognition mechanism between the GDM analogs and the target Hsp90. Combined analysis of anticancer test results (SKBR-3, SKOV-3, PC-3, U-87, A-549) and those performed in normal cells (HDF), KD values and docking modes at Hsp90 as well as clogP parameters, reveals that the rigid C(17)-arm (piperidyl, cyclohexyl) with a H-bond acceptor as carbonyl group together with a lipophilicity clogPâ¼3 favor high potency of analogs, even up to IC50 â¼0.08 µM, at improved selectivity (SIHDF > 30), when compared to GDM. The most active 25 show higher anticancer potency than 17-AAG (in SKOV-3 and A-549) as well as reblastatin (in SKBR-3 and SKOV-3). Opening of the ansa-bridge within GDM analogs, at the best case, decreases activity (IC50â¼2 µM) and toxicity in HDF cells (SIHDFâ¼2-3), relative to GDM.
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Base de dados:
MEDLINE
Assunto principal:
Benzoquinonas
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Lactamas Macrocíclicas
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Aminas
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Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article