Tumor inhibitors. LXXIII. Maytansine, a novel antileukemic ansa macrolide from Maytenus ovatus

Kupchan, S. Morris; Komoda, Yasuo; Court, William A.; Thomas, G.; Smith, Roger M.; Karim, Aziz; Gilmore, C. J.; Haltiwanger, R. C.; Bryan, R. F.

doi:10.1021/ja00759a054

Cited by 421 publications

(204 citation statements)

References 3 publications

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“…The conjugation of MF-T to the maytansinoid tubulin inhibitor DM4 through a hindered disulfide linker generated the antibody-drug conjugate anetumab ravtansine (BAY94-9343) (148). The uptake of the DM4 toxin causes inhibition of mitosis through targeting microtubule polymerization (149). Further, neighboring cells are also affected through a phenomenon known as "bystander cytotoxicity" where active drug metabolites diffuse into neighboring cells (150).…”

Section: Antibody-drug Conjugatesmentioning

confidence: 99%

Novel systemic therapy against malignant pleural mesothelioma

Mancuso

Neal

2017

Transl. Lung Cancer Res.

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Malignant pleural mesothelioma is an aggressive tumor of the pleura with an overall poor prognosis. Even with surgical resection, for which only a subset of patients are eligible, long term disease free survival is rare. Standard first-line systemic treatment consists of a platinum analog, an anti-metabolite, and sometimes anti-angiogenic therapy, but there is currently no well-established standard therapy for refractory or relapsed disease. This review focuses on efforts to develop improved systemic therapy for the treatment of malignant pleural mesothelioma (MPM) including cytotoxic systemic therapy, a variety of tyrosine kinase inhibitors and their downstream effector pathways, pharmacologic targeting of the epigenome, novel approaches to target proteins expressed on mesothelioma cells (such as mesothelin), arginine depletion therapy, and the emerging role of immunotherapy. Overall, these studies demonstrate the challenges of improving systemic therapy for MPM and highlight the need to develop therapeutic strategies to control this disease.

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Section: Antibody-drug Conjugatesmentioning

confidence: 99%

Novel systemic therapy against malignant pleural mesothelioma

Mancuso

Neal

2017

Transl. Lung Cancer Res.

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“…Resistance to these antibiotics develops easily due to mutations in the rpoB gene, calling for the development of next generation drugs to overcome this problem (Floss and Yu, 2005). The ansamitocins (Higashide et al, 1977), produced by the actinomycete, Actinosynnema pretiosum, belong to the family of the maytansinoids first isolated from higher plants ( Kupchan et al, 1972). They are notable for their extremely potent antitumor activity which is due to binding to the tubulin β-subunit, blocking the assembly of functional microtubules (Cassady et al, 2004).…”

Section: Halogenationsmentioning

confidence: 99%

Combinatorial biosynthesis—Potential and problems

Floss

2006

Journal of Biotechnology

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114

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Because of their ecological functions, natural products have been optimized in evolution for interaction with biological systems and receptors. However, they have not necessarily been optimized for other desirable drug properties and thus can often be improved by structural modification. Using examples from the literature, this paper reviews the opportunities for increasing structural diversity among natural products by combinatorial biosynthesis, i.e., the genetic manipulation of biosynthetic pathways. It distinguishes between combinatorial biosynthesis in a narrower sense to generate libraries of modified structures, and metabolic engineering for the targeted formation of specific structural analogs. Some of the problems and limitations encountered with these approaches are also discussed. Work from the author's laboratory on ansamycin antibiotics is presented which illustrates some of the opportunities and limitations. KeywordsCombinatorial biosynthesis; metabolic engineering; natural products; rifamycin; maytansinoids; polyketides Combinatorial biosynthesis can be defined as the application of genetic engineering to modify biosynthetic pathways to natural products in order to produce new and altered structures using nature's biosynthetic machinery. The feasibility of this approach was first demonstrated in work by David Hopwood and colleagues (Hopwood et al., 1985). Following the cloning of the biosynthetic genes for the antibiotic actinorhodin from Streptomyces coelicolor (Malpartida & Hopwood, 1984), Hopwood and coworkers cloned some or all of these genes into the producers of the antibiotics medermycin (Takano et al., 1976) and dihydrogranaticin (Corbaz et al., 1957), respectively. The transformant of the medermycin producer, Streptomyces sp. AM-7161 produced, in addition to medermycin, large amounts of a new compound, mederrhodin A, which carried an additional hydroxy group characteristic of actinorhodin ( Figure 1). The transformant of the dihydrogranaticin producer, Streptomyces violaceoruber Tü 22 produced a new compound, dihydrogranatirhodin, which has the actinorhodin configuration at one and the dihydrogranaticin configuration at the other stereocenter of the isochromane quinone system. This work represents the first, albeit modest, implementation of the concept of combinatorial biosynthesis of natural products. Since then, a large number of examples encompassing a wide range of natural product classes have appeared in the literature, and this approach has been accepted as a useful tool to increase the chemical diversity of natural products (Staunton and Wilkinson, 2001;Walsh, 2002;Rix et al., 2002;Reeves, 2003). Following the author's primary interests, this article focuses on the application of the combinatorial biosynthesis approach to microbial natural products and within these to Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript ...

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“…1) are extraordinarily potent antitumor agents that were originally isolated from members of the higher plant families Celastraceae, Rhamnaceae, and Euphorbiaceae, as well as some mosses, under the auspices of the U.S. National Cancer Institute (1)(2)(3)(4)(5). They are 19-membered macrocyclic lactams related to ansamycin antibiotics of microbial origin, such as rifamycin B and geldanamycin (6).…”

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confidence: 99%

The biosynthetic gene cluster of the maytansinoid antitumor agent ansamitocin from Actinosynnema pretiosum

Bai

Clade

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

279

256

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Maytansinoids are potent antitumor agents found in plants and microorganisms. To elucidate their biosynthesis at the biochemical and genetic level and to set the stage for their structure modification through genetic engineering, we have cloned two gene clusters required for the biosynthesis of the maytansinoid, ansamitocin, from a cosmid library of Actinosynnema pretiosum ssp. auranticum ATCC 31565. This is a rare case in which the genes involved in the formation of a secondary metabolite are dispersed in separate regions in an Actinomycete. A set of genes, asm22-24, asm43-45, and asm47, was identified for the biosynthesis of the starter unit, 3-amino-5-hydroxybenzoic acid (AHBA). Remarkably, there are two AHBA synthase gene homologues, which may have different functions in AHBA formation. Four type I polyketide synthase genes, asmA-D, followed by the downloading asm9, together encode eight homologous sets of enzyme activities (modules), each catalyzing a specific round of chain initiation, elongation, or termination steps, which assemble the ansamitocin polyketide backbone. Another set of genes, asm13-17, encodes the formation of an unusual ''methoxymalonate'' polyketide chain extension unit that, notably, seems to be synthesized on a dedicated acyl carrier protein rather than as a CoA thioester. Additional ORFs are involved in postsynthetic modifications of the initial polyketide synthase product, which include methylations, an epoxidation, an aromatic chlorination, and the introduction of acyl and carbamoyl groups. Tentative functions of several asm genes were confirmed by inactivation and heterologous expression.

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Tumor inhibitors. LXXIII. Maytansine, a novel antileukemic ansa macrolide from Maytenus ovatus

Cited by 421 publications

References 3 publications

Novel systemic therapy against malignant pleural mesothelioma

Novel systemic therapy against malignant pleural mesothelioma

Combinatorial biosynthesis—Potential and problems

The biosynthetic gene cluster of the maytansinoid antitumor agent ansamitocin from Actinosynnema pretiosum

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