RESUMEN
Several Hsp90 modulators have been identified including the N-terminal ligand geldanamycin (GDA), the C-terminal ligand novobiocin (NB), and the co-chaperone disruptor celastrol. Other Hsp90 modulators elicit a mechanism of action that remains unknown. For example, the natural product gedunin and the synthetic anti-spermatogenic agent H2-gamendazole, recently identified Hsp90 modulators, manifest biological activity through undefined mechanisms. Herein, we report a series of biochemical techniques used to classify such modulators into identifiable categories. Such studies provided evidence that gedunin and H2-gamendazole both modulate Hsp90 via a mechanism similar to celastrol, and unlike NB or GDA.
Asunto(s)
Proteínas HSP90 de Choque Térmico/efectos de los fármacos , Benzoquinonas/farmacología , Línea Celular Tumoral , Cromatografía de Afinidad , Proteínas HSP90 de Choque Térmico/química , Humanos , Hidrólisis , Inmunoprecipitación , Lactamas Macrocíclicas/farmacología , Modelos Moleculares , Novobiocina/farmacología , Triterpenos Pentacíclicos , Triterpenos/farmacologíaRESUMEN
The molecular chaperone Hsp90 requires the assistance of immunophilins, co-chaperones, and partner proteins for the conformational maturation of client proteins. Hsp90 inhibition represents a promising anticancer strategy due to the dependence of numerous oncogenic signaling pathways upon Hsp90 function. Historically, small molecules have been designed to inhibit ATPase activity at the Hsp90 N-terminus; however, these molecules also induce the pro-survival heat shock response (HSR). Therefore, inhibitors that exhibit alternative mechanisms of action that do not elicit the HSR are actively sought. Small molecules that disrupt Hsp90-co-chaperone interactions can destabilize the Hsp90 complex without induction of the HSR, which leads to inhibition of cell proliferation. In this article, selective inhibition of F1F0 ATP synthase by cruentaren A was shown to disrupt the Hsp90-F1F0 ATP synthase interaction and result in client protein degradation without induction of the HSR.
Asunto(s)
Proteínas HSP90 de Choque Térmico/química , Macrólidos/metabolismo , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Western Blotting , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Humanos , Concentración 50 Inhibidora , Células MCF-7 , Macrólidos/farmacología , ATPasas de Translocación de Protón Mitocondriales/efectos de los fármacos , Estructura Molecular , Unión Proteica , Pliegue de ProteínaRESUMEN
Cruentaren A, an antifungal benzolactone produced by the myxobacterium Byssovorax cruenta, is highly cytotoxic against various human cancer cell lines and a highly selective inhibitor of mitochondrial F-ATPase. A convergent and efficient synthesis of cruentaren A is reported, based upon a diastereoselective alkylation, a series of stereoselective aldol reactions utilizing Myers' pseudoephedrine propionamide, an acyl bromide mediated esterification, and a ring-closing metathesis (RCM) as the key steps. The RCM reaction was applied for the first time toward the total synthesis of cruentaren A, which led to a convergent and efficient synthesis of the natural product.
Asunto(s)
Macrólidos/síntesis química , Alquilación , Antifúngicos , Humanos , Macrólidos/química , Macrólidos/farmacología , ATPasas de Translocación de Protón Mitocondriales/antagonistas & inhibidores , Estructura Molecular , Myxococcales/química , EstereoisomerismoRESUMEN
Macrocyclic natural products are a powerful class of lead-like chemical entities. Despite commonly violating Lipinski's "rule of 5", these compounds often demonstrate superior drug-like physicochemical and pharmacokinetic attributes when compared to their acyclic counterparts. However, the elaborate structural architectures of such molecules require rigorous synthetic investigation that complicates analogue development and their application to drug discovery programs. To circumvent these limitations, a conformation-based approach using limited SAR and molecular modeling was implemented to design simplified analogues of trienomycin A, in which the corresponding analogues could be prepared in a succinct manner to rapidly identify essential structural components necessary for biological activity. Trienomycin A is a member of the ansamycin family of natural products that possesses potent anticancer activity. These studies revealed a novel trienomycin A analogue, monoenomycin, which manifests potent anticancer activity.
RESUMEN
Development of the DNA gyrase inhibitor, novobiocin, into a selective Hsp90 inhibitor was accomplished through structural modifications to the amide side chain, coumarin ring, and sugar moiety. These species exhibit â¼700-fold improved anti-proliferative activity versus the natural product as evaluated by cellular efficacies against breast, colon, prostate, lung, and other cancer cell lines. Utilization of structure-activity relationships established for three novobiocin synthons produced optimized scaffolds, which manifest midnanomolar activity against a panel of cancer cell lines and serve as lead compounds that manifest their activities through Hsp90 inhibition.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Cumarinas/química , Diseño de Fármacos , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Novobiocina/análogos & derivados , Antibacterianos/química , Antibacterianos/farmacología , Antineoplásicos/química , Carbohidratos/química , Línea Celular Tumoral , Cumarinas/farmacología , Femenino , Proteínas HSP90 de Choque Térmico/química , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Masculino , Estructura Molecular , Terapia Molecular Dirigida , Novobiocina/química , Novobiocina/farmacología , Relación Estructura-ActividadRESUMEN
The 90 kDa heat shock protein (Hsp90) has become a validated target for the development of anti-cancer agents. Several Hsp90 inhibitors are currently under clinical trial investigation for the treatment of cancer. All of these agents inhibit Hsp90's protein folding activity by binding to the N-terminal ATP binding site of the Hsp90 molecular chaperone. Administration of these investigational drugs elicits induction of the heat shock response, or the overexpression of several Hsps, which exhibit antiapoptotic and pro-survival effects that may complicate the application of these inhibitors. To circumvent this issue, alternate mechanisms for Hsp90 inhibition that do not elicit the heat shock response have been identified and pursued. After providing background on the structure, function, and mechanism of the Hsp90 protein folding machinery, this review describes several mechanisms of Hsp90 modulation via small molecules that do not induce the heat shock response.
Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/metabolismo , Neoplasias/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Adenosina Trifosfato/química , Adenosina Trifosfato/metabolismo , Animales , Proteínas HSP90 de Choque Térmico/química , Humanos , Neoplasias/química , Neoplasias/metabolismo , Enfermedades Neurodegenerativas/metabolismoRESUMEN
Conformationally constrained cis-amide chimeric inhibitors of Hsp90 have been synthesized and evaluated for their Hsp90 inhibitory activity. These new compounds exhibited Hsp90 ATPase inhibition and induced Hsp90-dependent client protein degradation in a dose-dependent manner. Biological data reported herein suggests that amide bond isomerization of geldanamycin derivatives plays an important role in affinity for the heteroprotein complex present in cancer cells.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Adenosina Trifosfatasas/antagonistas & inhibidores , Amidas/química , Antineoplásicos/química , Benzoquinonas/farmacología , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Lactamas Macrocíclicas/farmacología , Estructura Molecular , EstereoisomerismoRESUMEN
Gedunin (1), a tetranortriterpenoid isolated from the Indian neem tree ( Azadirachta indica), was recently shown to manifest anticancer activity via inhibition of the 90 kDa heat shock protein (Hsp90) folding machinery and to induce the degradation of Hsp90-dependent client proteins similar to other Hsp90 inhibitors. The mechanism of action by which gedunin induces client protein degradation remains undetermined, however, prior studies have demonstrated that it does not bind competitively versus ATP. In an effort to further probe the mechanism of action, 19 semisynthetic derivatives of gedunin were prepared and their antiproliferative activity against MCF-7 and SkBr3 breast cancer cells determined. Although no compound was found to exhibit antiproliferative activity more effective than the natural product, functionalities critical for antiproliferative activity have been identified.