Molecularly targeted natural products discovery from diverse natural sources

我们的研究努力将基于分子靶标的发现与天然产品化学相结合。天然产物是结构复杂性和生物活性的来源，可以提供对新靶点、途径或作用模式的功能的洞察。它们在解剖和了解癌症发展、进展和治疗的复杂性方面发挥着重要作用，因此持续的发现努力非常适合新的潜在抗癌应用。我们致力于发现和定义在特定生物系统中活跃的化合物的化学，即那些有效调节感兴趣的分子靶标的化合物，无论它们是新的还是以前已知的化学实体。因此，制定了适当的策略来选择、优先排序、生物测定引导的分馏和活性提取物的去掉，以促进有效的铅识别。与我们的同事和合作者合作，我们成功地开展了识别激活蛋白-1(AP-1)抑制物的研究，AP-1是一种与肿瘤促进和进展相关的致癌转录因子。我们的目标是找到在广泛的浓度范围内抑制AP-1的化合物，然后再导致细胞毒性。从这些提取物中总共分离和鉴定了29个活性化合物，其中24个来自植物来源，2个来自海洋无脊椎动物，2个来自蓝藻，1个来自真菌提取物。我们获得的最有希望的AP-1抑制剂是一种名为洋葱碱的植物生物碱。它是一种低微摩尔的AP-1抑制剂，能特异性地阻断AP-1依赖基因的转录激活，并减少转移癌细胞系的细胞迁移和侵袭。一项旨在发现多药耐药转运蛋白抑制剂的天然产品筛选工作，称为三磷酸腺苷结合盒蛋白G2(ABCG2)，提供了海洋生物碱Botryllamide G作为先导开发化合物。Botryllamide G对ABCG2介导的药物转运具有较强的抑制作用，且细胞毒活性较低。它似乎是ABCG2的真正抑制物，而不是竞争性底物，它结合并改变转运蛋白的构象，从而破坏其外流功能。开发了一种博特莱胺的合成方法，目前正在进行体内临床前开发研究。对致癌转录因子缺氧诱导因子2α(HIF-2α)抑制剂的筛选活动确定了31种活性提取物，并进行了生物测定指导的分级研究。我们获得了55个纯化化合物，其中33个被提供给我们的CCR合作者进行正在进行的二次生物学评估。可以抑制人类免疫缺陷病毒(HIV)进入细胞或复制的天然产品也令人感兴趣。从多种陆生植物和海洋来源中分离和鉴定了新的HIV抑制环肽。

Our research efforts combine molecular target-based discovery with natural products chemistry. Natural products are a source of structural complexity and biological activity that can provide insight on the function of new targets, pathways, or modes of action. They play an important role in dissecting and understanding the intricacies of cancer development, progression, and treatment so continued discovery efforts are highly appropriate for new potential anticancer applications. We work to discover and define the chemistry of compounds that are active in a particular biological system, meaning those that effectively modulate the molecular target of interest, regardless of whether they are new or previously known chemical entities. Thus, appropriate strategies for the selection, prioritization, bioassay-guided fractionation, and dereplication of active extracts were developed to facilitate efficient lead identification. Working in conjunction with our colleagues and collaborators, we successfully undertook studies to identify inhibitors of Activator Protein-1 (AP-1) an oncogenic transcription factor associated with tumor promotion and progression. Our goal was to find compounds that inhibited AP-1 over a broad concentration range before they resulted in cytotoxicity.A total of 29 active compounds were isolated and identified from these extracts with 24 from plant sources, 2 from a marine invertebrate, 2 from a cyanobacterium, and 1 from a fungal extract. The most promising AP-1 inhibitor we obtained was a plant alkaloid known as cephaeline. It is a low micromolar inhibitor of AP-1 that specifically blocked transcriptional activation of AP-1 dependent genes and reduced cellular migration and invasion by a metastatic cancer cell line. A natural product screening effort to discover inhibitors of the multidrug resistance transporter known as Adenosine triphosphate-Binding Cassette protein G2 (ABCG2) provided the marine alkaloid botryllamide G as the lead development compound. Botryllamide G exhibited robust inhibition of ABCG2-mediated drug transport and low cytotoxic activity. It appears to function as a true inhibitor of ABCG2 and not a competitive substrate, that binds to and alters the conformation of the transporter that disrupts its efflux function. A synthesis of botryllamide was developed and it is now undergoing in vivo preclinical development studies.A screening campaign for inhibitors of the oncogenic transcription factor Hypoxia Inducible Factor 2 alpha (HIF-2alpha) identified 31 active extracts that were subjected to bioassay-guided fractionation studies. Fifty five purified compounds were obtained and 33 were provided to our CCR collaborators for ongoing secondary biological evaluation.Natural products that can inhibit the cellular entry or replication of the human immunodeficiency virus (HIV) are also of interest. Novel HIV inhibitory cyclicpeptides have been isolated and identified from a variety of terrestrial plant and marine sources.