RESUMO
Azobenzene functionalized peptides are of great importance in photoresponsive biosystems and photopharmacology. Herein, we report an efficient approach to prepare azobenzene functionalized peptides through late-stage modification of tyrosine-containing peptides using a dearomatization-rearomatization strategy. This approach shows good chemoselectivity and site selectivity as well as sensitive group tolerance to various peptides. This method enriches the postsynthetic modification toolbox of peptides and has great potential to be applied in medicinal chemistry and chemical biology.
Assuntos
Compostos Azo/química , Peptídeos/síntese química , Tirosina/química , Estrutura Molecular , Peptídeos/químicaRESUMO
Coibamide A (1) is a highly N-methylated cyclodepsipeptide with low nanomolar antiproliferative activities against various cancer cell lines. In previous work, we discovered a simplified analogue, [MeAla3-MeAla6]-coibamide (1a), which exhibited the same inhibitory abilities as coibamide A. Herein, to reduce the whole-body toxicity and improve the solubility of 1a, two novel peptide-drug conjugates RGD-SS-CA (2) and RGD-VC-CA (3) were designed, synthesized, and evaluated. Composed of cyclodepsipeptide 1a, a tumor-homing RGD motif, and a conditionally labile linker, the conjugates are expected to release 1a tracelessly in specific tumor microenvironments. Compared with RGD-VC-CA (3), RGD-SS-CA (2) proved to be superior in in vitro drug release and cytotoxicity tests. Notably, intravenous injection of RGD-SS-CA (2) into mice-bearing human tumor xenografts induced significant tumor growth suppression with negligible toxicity. Therefore, as a novel prodrug of the coibamide A analogue, conjugate 2 has great potential for further exploration in cancer drug discovery.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Depsipeptídeos/síntese química , Depsipeptídeos/farmacologia , Animais , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Depsipeptídeos/química , Depsipeptídeos/toxicidade , Desenho de Fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pró-Fármacos/farmacologia , Solubilidade , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
To enable the large-scale synthesis of coibamide A, we developed an improved synthetic strategy for this class of cyclodepsipeptide. The versatility of the synthetic procedure was demonstrated by the preparation of a series of designed coibamide A analogues, which enabled the preliminary structure-activity relationship (SAR) studies for this compound. Although most modifications of coibamide A resulted in decrease or loss of the antiproliferativity, we found that versatile substitution at position 3 was well tolerated. Remarkably, a simplified analogue, [MeAla3-MeAla6]-coibamide (1f), not only showed nearly the same inhibition as coibamide A against the tested cancer cells but also significantly inhibited tumor growth in vivo. The improved synthetic strategy and the relevant trends of SAR disclosed in this study will be valuable for further optimization of the overall profile of coibamide A.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Depsipeptídeos/química , Depsipeptídeos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Depsipeptídeos/síntese química , Feminino , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Epstein-Barr virus (EBV) establishes latent infection and is associated with several types of lymphomas and carcinomas. EBV nuclear antigen 1 (EBNA1) is expressed in all EBV-positive tumor cells. EBNA1 binds to the origin of virus plasmid replication (OriP) on the EBV episome to initiate virus DNA replication and regulates virus gene expression as a transcriptional activator. In this study, we designed and synthesized a pyrrole-imidazole polyamide-Hoechst 33258 conjugate named EIP-2 (2), which specifically binds to the OriP region with high affinity, to interrupt EBNA1-OriP binding in vitro and in vivo. By eradicating the EBV episome in EBV-positive cells, compound 2 selectively inhibited EBV-positive cell proliferation. Moreover, the injection of 2 significantly suppressed tumor growth in the mice xenograft tumor model. These findings demonstrate that compound 2 is a potential therapeutic candidate for the treatment of EBV-associated tumors.