Medicinal Chemistry and Chemical Biology of Diketopiperazine-Type Antimicrotubule and Vascular-Disrupting Agents

Hayashi, Yoshio; Yamazaki-Nakamura, Yuri; Yakushiji, Fumika

doi:10.1248/cpb.c13-00404

Cited by 32 publications

(12 citation statements)

References 51 publications

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“…For example, diketopiperazines have found therapeutic application in the treatment of erectile dysfunction as inhibitors of phosphodiesterase-5 [11], as well as antagonists of oxytocin for the treatment of preterm labor [12]. Another significant example is the vascular disrupting and tubulin-depolymerizing agent plinabulin, based on the marine fungal agent halimide, and currently on the last stage of clinical development for the treatment of non-small-cell lung cancer (NSCLC) [13,14,15]. The diketopiperazine-derived template has been also investigated as a brain shuttle for the delivery of medicinal agents with limited ability to cross the blood-brain barrier, bypassing the limited bioavailability of several drugs [16,17].…”

Section: General Considerationsmentioning

confidence: 99%

Double the Chemistry, Double the Fun: Structural Diversity and Biological Activity of Marine-Derived Diketopiperazine Dimers

et al. 2019

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While several marine natural products bearing the 2,5-diketopiperazine ring have been reported to date, the unique chemistry of dimeric frameworks appears to remain neglected. Frequently reported from marine-derived strains of fungi, many naturally occurring diketopiperazine dimers have been shown to display a wide spectrum of pharmacological properties, particularly within the field of cancer and antimicrobial therapy. While their structures illustrate the unmatched power of marine biosynthetic machinery, often exhibiting unsymmetrical connections with rare linkage frameworks, enhanced binding ability to a variety of pharmacologically relevant receptors has been also witnessed. The existence of a bifunctional linker to anchor two substrates, resulting in a higher concentration of pharmacophores in proximity to recognition sites of several receptors involved in human diseases, portrays this group of metabolites as privileged lead structures for advanced pre-clinical and clinical studies. Despite the structural novelty of various marine diketopiperazine dimers and their relevant bioactive properties in several models of disease, to our knowledge, this attractive subclass of compounds is reviewed here for the first time.

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Section: General Considerationsmentioning

confidence: 99%

Double the Chemistry, Double the Fun: Structural Diversity and Biological Activity of Marine-Derived Diketopiperazine Dimers

et al. 2019

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“…A large number of analogs of this lead compound have been prepared with a view to improve its potency and aqueous solubility. 48 Plinabulin derivatives probably do not interact with the colchicine binding site. Instead, they interact with the boundary region between the α-and β-tubulins around the colchicine site.…”

Section: Compounds Binding At the Colchicine Sitementioning

confidence: 99%

Anticancer Drugs Targeting Tubulin and Microtubules

Avendaño

2015

Medicinal Chemistry of Anticancer Drugs

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“…This compound, a simple modification of the terrestrial and also marine fungal metabolite halimide [88], entered Phase II clinical trials under Nereus Pharmaceuticals (San Diego, CA, USA). Two completed trials under that sponsor are shown in the NIH database, one at Phase I and the other at Phase I/II.…”

Section: Other Marine-derived Compounds In Clinical Trials Againstmentioning

confidence: 99%

Marine-Sourced Anti-Cancer and Cancer Pain Control Agents in Clinical and Late Preclinical Development

2014

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The marine habitat has produced a significant number of very potent marine-derived agents that have the potential to inhibit the growth of human tumor cells in vitro and, in a number of cases, in both in vivo murine models and in humans. Although many agents have entered clinical trials in cancer, to date, only Cytarabine, Yondelis® (ET743), Eribulin (a synthetic derivative based on the structure of halichondrin B), and the dolastatin 10 derivative, monomethylauristatin E (MMAE or vedotin) as a warhead, have been approved for use in humans (Adcetris®). In this review, we show the compounds derived from marine sources that are currently in clinical trials against cancer. We have included brief discussions of the approved agents, where they are in trials to extend their initial approved activity (a common practice once an agent is approved), and have also included an extensive discussion of the use of auristatin derivatives as warheads, plus an area that has rarely been covered, the use of marine-derived agents to ameliorate the pain from cancers in humans, and to act as an adjuvant in immunological therapies.

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Medicinal Chemistry and Chemical Biology of Diketopiperazine-Type Antimicrotubule and Vascular-Disrupting Agents

Abstract: Certain antimicrotubule agents displaying colchicine-like tubulin-depolymerizing activity can act as both cytotoxic and vascular-disrupting agents (VDAs

Cited by 32 publications

References 51 publications

Double the Chemistry, Double the Fun: Structural Diversity and Biological Activity of Marine-Derived Diketopiperazine Dimers

Double the Chemistry, Double the Fun: Structural Diversity and Biological Activity of Marine-Derived Diketopiperazine Dimers

Anticancer Drugs Targeting Tubulin and Microtubules

Marine-Sourced Anti-Cancer and Cancer Pain Control Agents in Clinical and Late Preclinical Development

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