RESUMO
The promotion of apoptosis in tumor cells is a popular strategy for developing anti-cancer drugs. Here, we demonstrate that the plant indole alkaloid natural product nauclefine induces apoptosis of diverse cancer cells via a PDE3A-SLFN12 dependent death pathway. Nauclefine binds PDE3A but does not inhibit the PDE3A's phosphodiesterase activity, thus representing a previously unknown type of PDE3A modulator that can initiate apoptosis without affecting PDE3A's canonical function. We demonstrate that PDE3A's H840, Q975, Q1001, and F1004 residues-as well as I105 in SLFN12-are essential for nauclefine-induced PDE3A-SLFN12 interaction and cell death. Extending these molecular insights, we show in vivo that nauclefine inhibits tumor xenograft growth, doing so in a PDE3A- and SLFN12-dependent manner. Thus, beyond demonstrating potent cytotoxic effects of an alkaloid natural product, our study illustrates a potentially side-effect-reducing strategy for targeting PDE3A for anti-cancer therapeutics without affecting its phosphodiesterase activity.
Assuntos
Alcaloides/farmacologia , Apoptose/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Indóis/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Naftiridinas/farmacologia , Alcaloides/química , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cilostazol/farmacologia , Feminino , Humanos , Indóis/química , Camundongos Nus , Naftiridinas/química , Inibidores da Fosfodiesterase 3/farmacologia , Estabilidade Proteica/efeitos dos fármacos , Tetra-Hidroisoquinolinas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A flexible strategy for constructing natural products containing indolizinone or quinolizinone scaffolds and their analogues was developed, which was based on a cascade exoâ hydroamination followed by spontaneous lactamization. This method was applied in the total synthesis of camptothecin in nine steps in a new ring-forming approach. It was also used to efficiently prepare five biogenetically or structurally related natural alkaloids, including 22-hydroxyacuminatine, oxypalmatine, norketoyobyrine, naucleficine, and nauclefine, as well as 35 natural-product-like molecules. We believe that this method and the small-molecule library prepared with it can open new avenues for studying the bioactivity of camptothecin and Nauclea natural products.
Assuntos
Produtos Biológicos/síntese química , Camptotecina/síntese química , Produtos Biológicos/química , Camptotecina/química , Estrutura Molecular , EstereoisomerismoRESUMO
Total synthesis of cryptocin, a fungus metabolite, was achieved based on the biosynthetic hypothesis. A variety of derivatives of cryptocin, equisetin and fusarisetin A were prepared, wherein the racemization of C-3 and diastereoselectivity of C-5 were investigated. We further examined their inhibitory effects on breast cancer cell survival and metastasis, and summarized the structure-activity relationship.