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1.
J Am Chem Soc ; 142(35): 15107-15115, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32701272

RESUMO

Epithiodiketopiperazines (ETPs) are a structurally complex class of fungal natural products with potent anticancer activity. In ETPs, the diketopiperazine ring is spanned by a disulfide bond that is constrained in a high-energy eclipsed conformation. We employed computational, synthetic, and spectroscopic methods to investigate the physicochemical attributes of this atypical disulfide bond. We find that the disulfide bond is stabilized by two n→π* interactions, each with large energies (3-5 kcal/mol). The n→π* interactions in ETPs make disulfide reduction much more difficult, endowing stability in physiological environments in a manner that could impact their biological activity. These data reveal a previously unappreciated means to stabilize a disulfide bond and highlight the utility of the n→π* interaction in molecular design.


Assuntos
Teoria da Densidade Funcional , Dissulfetos/química , Piperazinas/química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , Oxirredução , Termodinâmica
2.
J Org Chem ; 85(7): 4648-4662, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32126173

RESUMO

We describe our design, synthesis, and chemical study of a set of functional epidithiodiketopiperazines (ETPs) and evaluation of their activity against five human cancer cell lines. Our structure-activity relationship-guided substitution of ETP alkaloids offers versatile derivatization while maintaining potent anticancer activity, offering exciting opportunity for their use as there are no examples of complex and potently anticancer (nM) ETPs being directly used as conjugatable probes or warheads. Our synthetic solutions to strategically designed ETPs with functional linkers required advances in stereoselective late-stage oxidation and thiolation chemistry in complex settings, including the application of novel reagents for dihydroxylation and cis-sulfidation of diketopiperazines. We demonstrate that complex ETPs equipped with a strategically substituted azide functional group are readily derivatized to the corresponding ETP-triazoles without compromising anticancer activity. Our chemical stability studies of ETPs along with cytotoxic evaluation of our designed ETPs against A549, DU 145, HeLa, HCT 116, and MCF7 human cancer cell lines provide insights into the impact of structural features on potency and chemical stability, informing future utility of ETPs in chemical and biological studies.


Assuntos
Antineoplásicos , Piperazinas , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Dicetopiperazinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Piperazinas/farmacologia , Relação Estrutura-Atividade
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