Department of Chemistry , Indiana University , Bloomington , Indiana 47405 , United States.
Acc Chem Res. 2019 Jul 16;52(7):1957-1967. doi: 10.1021/acs.accounts.9b00185. Epub 2019 Jun 25.
The predictable and controllable interaction of small organic or peptidic molecules with biological substrates is the primary reason most pharmaceuticals are narrowly decorated carbon frameworks. The inhibition or activation binding models are measurable and without side reactions that can cause pathological angst. Yet many diseases, especially those involving rapid proliferation of cells (i.e., cancer) or aggregation of peptides (e.g., heart disease, Alzheimer's disease) have not yet been cured by inhibition therapeutics. Additionally, interventional medicine is often required to alleviate such maladies by physical removal first, followed by molecular-level therapy as a second stage. Thus, there appears to be a niche for more aggressive therapeutics that may employ harsher chemical processes to realize clinical efficacy, albeit without causing catastrophic side effects. Molecules that may be considered for this challenge are not typically biomimetic, nor do they fit the traditional pharmaceutical paradigm. They may have unusual modes of action or undesired reactivity that can be lethal if not controlled. These are the outliers; potential pharmacophores that biology does not know how to manage or adapt to. This is why they may be an intriguing class of agents that needs continuous development. In this Account, we connect the under-developed enediyne family of compounds and our metalloenediyne derivatives to existing radical-based therapeutics such as bleomycin and doxorubicin to illustrate that controlled diradical reactivity, although an outlier mechanism, has a place in the therapeutic portfolio. This is self-evident in that of the 11 natural product enediynes known, 2 have clinical impact, a strong ratio. We expand on the chemical diversity of potential enediyne constructs and focus on the accessible trigger mechanisms to activate diradical formation as a method to control toxicity. Moreover, we further illustrate how electromagnetic fields can be employed to activate both molecular and larger nanomaterial constructs that carry highly concentrated payloads of reactive reagent. Finally, we describe how controlled diradical reactivity can reach beyond traditional therapeutic targets such as DNA, to peptide aggregates found in blood clots, neural fibrils, and membrane scaffolds. It is our belief that cleverly constructed frameworks with well-designed and controlled activation/reaction schemes can lead to novel therapeutics that can challenge evolving viral and bacterial invaders. From this evangelical perspective, our hope is that the conceptual framework, if not the specific designs in this Account, stimulate the readership to develop out-of-the-box therapeutic designs that may combat resistant disease targets.
小分子有机或肽类分子与生物基质的可预测和可控相互作用是大多数药物仅为精心修饰的碳框架的主要原因。抑制或激活结合模型是可测量的，没有可能导致病理焦虑的副作用。然而，许多疾病，特别是涉及细胞快速增殖（如癌症）或肽聚集（如心脏病、阿尔茨海默病）的疾病，尚未通过抑制疗法治愈。此外，通常需要介入医学通过物理去除首先来缓解这种疾病，然后作为第二阶段进行分子水平治疗。因此，似乎需要更积极的治疗方法来填补这一空白，这些方法可能采用更苛刻的化学过程来实现临床疗效，尽管不会引起灾难性的副作用。用于此类挑战的分子通常不是仿生的，也不符合传统的药物范例。它们可能具有不寻常的作用方式或不希望的反应性，如果不加以控制，可能是致命的。这些是异常值;生物学不知道如何管理或适应的潜在药效团。这就是为什么它们可能是一类有趣的需要不断发展的药物。在本说明中，我们将未充分开发的烯二炔家族化合物及其金属烯二炔衍生物与现有的基于自由基的治疗剂（如博来霉素和阿霉素）联系起来，说明尽管控制双自由基反应性是一种异常机制，但它在治疗方案中占有一席之地。这在以下事实中显而易见：在已知的 11 种天然烯二炔中，有 2 种具有临床影响，这是一个很强的比例。我们扩展了潜在烯二炔结构的化学多样性，并侧重于可访问的触发机制，以激活双自由基形成作为控制毒性的方法。此外，我们进一步说明了如何利用电磁场来激活携带高浓度反应试剂的分子和更大的纳米材料构建体。最后，我们描述了控制双自由基反应性如何超越传统的治疗靶点，如 DNA，到达血液凝块、神经原纤维和膜支架中发现的肽聚集物。我们相信，通过精心构建的框架和精心设计的控制激活/反应方案，可以开发出新颖的治疗方法，这些方法可以挑战不断进化的病毒和细菌侵略者。从这个福音派的角度来看，我们希望，如果不是本说明中的具体设计，这个概念框架能激发读者开发出可能对抗耐药疾病靶点的新颖治疗设计。
