Efficient, divergent synthesis of cryptophycin unit A analogues

Bolduc, Kyle L.; Larsen, Scott D.; Sherman, David H.

doi:10.1039/c2cc32417b

Cited by 21 publications

(7 citation statements)

References 36 publications

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“…CrpD-M2 was successfully used to form secocryptophycin intermediates as well as cyclized cryptophycins 3, 24 and 51 using synthetic SNAC-ABC chain elongation intermediates as substrates. 105,106 This was the first study in which a NRPS with an embedded KR domain was utilized to generate bioactive compounds from natural and synthetic chain elongation intermediates, and should enable production of new cryptophycin analogous with improved bioactivity.…”

Section: Chemoenzymatic Synthesis Of Cryptophycin Analoguesmentioning

confidence: 99%

Unique marine derived cyanobacterial biosynthetic genes for chemical diversity

et al. 2016

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Cyanobacteria are a prolific source of structurally unique and biologically active natural products that derive from intriguing biochemical pathways. Advancements in genome sequencing have accelerated the identification of unique modular biosynthetic gene clusters in cyanobacteria and reveal a wealth of unusual enzymatic reactions involved in their construction. This article examines several interesting mechanistic transformations involved in cyanobacterial secondary metabolite biosynthesis with a particular focus on marine derived modular polyketide synthases (PKS), nonribosomal peptide synthetases (NRPS) and combinations thereof to form hybrid natural products. Further, we focus on the cyanobacterial genus Moorea and the co-evolution of its enzyme cassettes that create metabolic diversity. Progress in the development of heterologous expression systems for cyanobacterial gene clusters along with chemoenzymatic synthesis makes it possible to create new analogs. Additionally, phylum-wide genome sequencing projects have enhanced the discovery rate of new natural products and their distinctive enzymatic reactions. Summarizing, cyanobacterial biosynthetic gene clusters encode for a large toolbox of novel enzymes that catalyze unique chemical reactions, some of which may be useful in synthetic biology.

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Section: Chemoenzymatic Synthesis Of Cryptophycin Analoguesmentioning

confidence: 99%

Unique marine derived cyanobacterial biosynthetic genes for chemical diversity

et al. 2016

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“…The first form discovered was epoxide cryptophycin 1, which showed antitumoral activity both in preclinical in vitro (colon, breast, ovarian, lung, and nasopharyngeal carcinomas) and in vivo (lung, breast, and prostate tumors) models. This has led to isolation and synthesis of cryptophycin analogs, divided into epoxides, chlorohydrins, and glycinate chlorohydrins [ 24 ] ( Figure 3 ).…”

Section: Microtubule-destabilizing Agentsmentioning

confidence: 99%

Stabilizing versus Destabilizing the Microtubules: A Double-Edge Sword for an Effective Cancer Treatment Option?

Fanale

Bronte

Passiglia

et al. 2015

Analytical Cellular Pathology

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Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In proliferating cells, they are essential components in the division process through the formation of the mitotic spindle. As a result of these functions, tubulin and microtubules are targets for anticancer agents. Microtubule-targeting agents can be divided into two groups: microtubule-stabilizing, and microtubule-destabilizing agents. The former bind to the tubulin polymer and stabilize microtubules, while the latter bind to the tubulin dimers and destabilize microtubules. Alteration of tubulin-microtubule equilibrium determines the disruption of the mitotic spindle, halting the cell cycle at the metaphase-anaphase transition and, eventually, resulting in cell death. Clinical application of earlier microtubule inhibitors, however, unfortunately showed several limits, such as neurological and bone marrow toxicity and the emergence of drug-resistant tumor cells. Here we review several natural and synthetic microtubule-targeting agents, which showed antitumor activity and increased efficacy in comparison to traditional drugs in various preclinical and clinical studies. Cryptophycins, combretastatins, ombrabulin, soblidotin, D-24851, epothilones and discodermolide were used in clinical trials. Some of them showed antiangiogenic and antivascular activity and others showed the ability to overcome multidrug resistance, supporting their possible use in chemotherapy.

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“…69 Recently, a divergent method for the synthesis of unit A phenyl modied cryptophycins was reported by Sherman and coworkers (Scheme 17). 68 In addition, a highly efficient synthesis of olenic unit A precursor 63 relying on iridiumcatalysed stereo-and enantioselective crotylation and chemoselective oxidative olenation was investigated. This common intermediate was coupled to different phenyl moieties, namely 4-H, 4-triuoromethyl, 4-methoxy, and 4-cyano.…”

Section: Modications In Unit Amentioning

confidence: 99%

Recent approaches for the synthesis of modified cryptophycins

2013

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Cryptophycins are a family of antimitotic depsipeptides with very high cytotoxicity even against multi-drug resistant (MDR) cancer cells. The first representative was isolated from cyanobacteria Nostoc sp. in 1990. Their bioactivity is based on their interaction with the protein tubulin. Cryptophycins were found to induce apoptosis due to inhibition of the microtubule dynamics. Consequently, cryptophycin analogues are considered as potential antitumour agents. Retrosynthetically, cryptophycins can be subdivided into four building blocks, namely units A-D, to be assembled in the total synthesis. Since the discovery of this compound class, numerous synthetic analogues have been designed for structure-activity relationship (SAR) studies. This review gives a critical overview on cryptophycins, while the main focus lies on the synthetic challenges of recently published cryptophycins, together with emerging concepts on cryptophycin bioconjugation and prodrug design.

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Efficient, divergent synthesis of cryptophycin unit A analogues

Cited by 21 publications

References 36 publications

Unique marine derived cyanobacterial biosynthetic genes for chemical diversity

Unique marine derived cyanobacterial biosynthetic genes for chemical diversity

Stabilizing versus Destabilizing the Microtubules: A Double-Edge Sword for an Effective Cancer Treatment Option?

Recent approaches for the synthesis of modified cryptophycins

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