The chemistry and biology of the maytansinoid antitumor agents

Kirschning, Andreas; Harmrolfs, Kirsten; Knobloch, Tobias

doi:10.1016/j.crci.2008.02.006

Cited by 44 publications

(27 citation statements)

References 62 publications

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“…Later work on compounds isolated from the bacterium, subsequently renamed as Actinosynnema pretiosum , demonstrated that they were in fact identical to those isolated from other plant genera. For further information on the maytansenoids, the reader should consult the review by Kirchning et al, in 2008 [33] and / or the chapter by Yu et al, in 2012 [34] as these cover the chemistry and biosynthesis of these compounds.…”

Section: The Role Of Traditional Medicine and Plants In Drug Discoverymentioning

confidence: 99%

Natural products: A continuing source of novel drug leads

Cragg

Newman

2013

Biochimica et Biophysica Acta (BBA) - General Subjects

2,396

1,525

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1. Background Nature has been a source of medicinal products for millennia, with many useful drugs developed from plant sources. Following discovery of the penicillins, drug discovery from microbial sources occurred and diving techniques in the 1970s opened the seas. Combinatorial chemistry (late 1980s), shifted the focus of drug discovery efforts from Nature to the laboratory bench. 2. Scope of Review This review traces natural products drug discovery, outlining important drugs from natural sources that revolutionized treatment of serious diseases. It is clear Nature will continue to be a major source of new structural leads, and effective drug development depends on multidisciplinary collaborations. 3. Major Conclusions The explosion of genetic information led not only to novel screens, but the genetic techniques permitted the implementation of combinatorial biosynthetic technology and genome mining. The knowledge gained has allowed unknown molecules to be identified. These novel bioactive structures can be optimized by using combinatorial chemistry generating new drug candidates for many diseases. 4 General Significance: The advent of genetic techniques that permitted the isolation / expression of biosynthetic cassettes from microbes may well be the new frontier for natural products lead discovery. It is now apparent that biodiversity may be much greater in those organisms. The numbers of potential species involved in the microbial world are many orders of magnitude greater than those of plants and multi-celled animals. Coupling these numbers to the number of currently unexpressed biosynthetic clusters now identified (>10 per species) the potential of microbial diversity remains essentially untapped.

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Section: The Role Of Traditional Medicine and Plants In Drug Discoverymentioning

confidence: 99%

Natural products: A continuing source of novel drug leads

Cragg

Newman

2013

Biochimica et Biophysica Acta (BBA) - General Subjects

2,396

1,525

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“…Immunoconjugates of AP-3 have shown much promise as target-specific cancer chemotherapeutic agents in clinical trials [2,12,13]. As the production of AP-3 in wild-type A. pretiosum is relatively low, there is interest in increasing the yield of AP-3.…”

Section: Introductionmentioning

confidence: 99%

Constitutive overexpression of asm2 and asm39 increases AP-3 production in the actinomycete Actinosynnema pretiosum

Chin

Wong

2009

J Ind Microbiol Biotechnol

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Constitutive overexpression of regulators in the ansamitocin biosynthetic cluster of Actinosynnema pretiosum was investigated as a strategy to increase the production of ansamitocin-P3 (AP-3), a clinically promising chemotherapeutic agent. Putative transcriptional regulators asm2, asm29, and asm34 as well as the putative regulatory protein asm39 were cloned into a single-site integrative vector and a multicopy replicative vector, pAP40 and pREP, respectively, and then transformed into A. pretiosum. Transformants overexpressing asm2 and asm39 in pREP showed an increase in ansamitocin production (1.3-fold over parental levels) in a bioassay screen. In shake-flask fermentations, the asm2 and asm39 overexpression transformants attained a maximum AP-3 titer of 33 and 52 mg/l, respectively, which were 1.6- and 2.5-fold higher than the blank vector control. The increase in AP-3 production for the asm2 overexpression transformant was unexpected, since prior reports suggested that Asm2 was a transcriptional repressor. The increase in production appeared to be dependent on the high expression levels achieved with the replicative vector, which may have disrupted the normal function of Asm2. Quantitative reverse-transcription polymerase chain reaction (RT-PCR) confirmed that asm2 and asm39 transcription levels were significantly higher in the transformants relative to the control, suggesting that the yield improvement was due to the transformed plasmids. This study demonstrates that deregulated overexpression of regulatory genes is a feasible strategy to increase AP-3 production in A. pretiosum.

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“…[4][5][6] They bind microtubules in a manner similar to the vinca alkaloids but are 20-to 100-fold more potent at blocking mitosis. The antitumor activity of maytansine 4, the plant derived ansamitocin derivative, was extensively evaluated in human clinical trials, [7] but although potent in vitro, maytansine displayed a poor therapeutic window in vivo.…”

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confidence: 99%

Combined Muta‐ and Semisynthesis: A Powerful Synthetic Hybrid Approach to Access Target Specific Antitumor Agents Based on Ansamitocin P3

Taft

Harmrolfs

Nickeleit

et al. 2011

Chemistry A European J

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Access of four new tumor specific folic acid/ansamitocin conjugates is reported that relies on a synthetic strategy based on the combination of mutasynthesis and semisynthesis. Two bromo-ansamitocin derivatives were prepared by mutasynthesis or by a modified fermentation protocol, respectively, that served as starting point for the semisynthetic introduction of an allyl amine linker under Stille conditions. A sequence of standard coupling steps introduced the pteroic acid/glutamic acid/cysteine unit to the modified ansamitocins. All new derivatives, including those that are expected to be generated after internalization of the folic acid/ansamitocin conjugates into the cancer cell and reductive cleavage of the disulfide linkage showed good to strong antiproliferative activity (IC(50) <10 nM) for different cancer cell lines. Finally, the four conjugates were exposed to two cancer cell lines [cervix carcinoma, KB-3-1 (FR+) and lung carcinoma, A-459 (FR-)], the latter devoid of the membrane-bound folic acid receptor (FR-). All four conjugates showed strong antiproliferative activity for the FR+ cancer cell line but were inactive against the FR- cell line. The synthetic strategy pursued is based on the combination of mutasynthesis and semisynthesis and proved to be powerful for accessing new ansamitocin derivatives that are difficult to prepare by total synthesis.

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The chemistry and biology of the maytansinoid antitumor agents

Cited by 44 publications

References 62 publications

Natural products: A continuing source of novel drug leads

Natural products: A continuing source of novel drug leads

Constitutive overexpression of asm2 and asm39 increases AP-3 production in the actinomycete Actinosynnema pretiosum

Combined Muta‐ and Semisynthesis: A Powerful Synthetic Hybrid Approach to Access Target Specific Antitumor Agents Based on Ansamitocin P3

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