Total Synthesis of Bryostatin 3

Ohmori, Ken; Ogawa, Yasuyuki; Obitsu, Tetsuo; Ishikawa, Yuichi; Nishiyama, Shigeru; Yamamura, Shosuke

doi:10.1002/1521-3773(20000703)39:13<2290::aid-anie2290>3.0.co;2-6

Cited by 157 publications

(13 citation statements)

References 2 publications

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“…Bryostatins are highly oxygenated marine macrolides with a polyacetate backbone [69], and more than 20 analogs have been isolated from the marine bryozoans Bugula neritina and Amathia convuluta [70]. Most of bryostatins possess antineoplastic activity in many cancer systems like M5076 sarcoma, L10AB cell, and mouse lymphogenous metastatic model SCID.…”

Section: Bryostatin and Derivativesmentioning

confidence: 99%

“…The synthesis of bryostatin analog 27 (Scheme 4a) without ring A and with simplified ring B was carried out by a convergent esterification-macrotransacetalization procedure to couple the recognition (C-17-C-27) and the spacer (C-1-C-16) domain fragments ( Figure 5) [70]. The synthetic pathway involves an allylation of an appropriate alcohol I to give the ether intermediate II.…”

Section: Bryostatin and Derivativesmentioning

confidence: 99%

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Marine Natural Products as Models to Circumvent Multidrug Resistance

et al. 2016

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Multidrug resistance (MDR) to anticancer drugs is a serious health problem that in many cases leads to cancer treatment failure. The ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which leads to premature efflux of drugs from cancer cells, is often responsible for MDR. On the other hand, a strategy to search for modulators from natural products to overcome MDR had been in place during the last decades. However, Nature limits the amount of some natural products, which has led to the development of synthetic strategies to increase their availability. This review summarizes the research findings on marine natural products and derivatives, mainly alkaloids, polyoxygenated sterols, polyketides, terpenoids, diketopiperazines, and peptides, with P-gp inhibitory activity highlighting the established structure-activity relationships. The synthetic pathways for the total synthesis of the most promising members and analogs are also presented. It is expected that the data gathered during the last decades concerning their synthesis and MDR-inhibiting activities will help medicinal chemists develop potential drug candidates using marine natural products as models which can deliver new ABC transporter inhibitor scaffolds.

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Section: Bryostatin and Derivativesmentioning

confidence: 99%

Section: Bryostatin and Derivativesmentioning

confidence: 99%

Marine Natural Products as Models to Circumvent Multidrug Resistance

et al. 2016

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“…The yields of bryostatin's related congeners are similarly low (10 −3 to 10 −8 %) (42), and seasonal variability has further complicated isolation. Although chemical synthesis offers a supply possibility, published syntheses of the clinical lead or similarly potent congeners (K i < 10 nM) have thus far been too long (>55 steps) to impact cost-effective supply (43)(44)(45)(46)(47). Similarly, engineered biosynthesis, although promising, is still in the early stages of development (48).…”

mentioning

confidence: 99%

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

Wender

Baryza

Brenner

et al. 2011

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

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Modern methods for the identification of therapeutic leads include chemical or virtual screening of compound libraries. Nature's library represents a vast and diverse source of leads, often exhibiting exquisite biological activities. However, the advancement of natural product leads into the clinic is often impeded by their scarcity, complexity, and nonoptimal properties or efficacy as well as the challenges associated with their synthesis or modification. Function-oriented synthesis represents a strategy to address these issues through the design of simpler and therefore synthetically more accessible analogs that incorporate the activity-determining features of the natural product leads. This study illustrates the application of this strategy to the design and synthesis of functional analogs of the bryostatin marine natural products. It is specifically directed at exploring the activity-determining role of bryostatin A-ring functionality on PKC affinity and selectivity. The resultant functional analogs, which were prepared by a flexible, modular synthetic strategy, exhibit excellent affinity to PKC and differential isoform selectivity. These and related studies provide the basic information needed for the design of simplified and thus synthetically more accessible functional analogs that target PKC isoforms, major targets of therapeutic interest.

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“…148 Mesmo assim, este ainda não é um processo economicamente viável para a produção em larga escala desta classe de substâncias. [149][150][151] No caso da briostatina, o derivado briolog é um exemplo de simplificação molecular e, consequentemente, de sua síntese, em que a atividade farmacológica é mantida. 90,152 Já a aquacultura da esponja Discoderma dissoluta, produtora do discodermolido, outro policetídeo, não foi bem sucedida e os esforços se concentram em aprimorar sua síntese, bem como a de seus análogos.…”

Section: Nsclc Melanoma E Carcinoma Hepatocelularunclassified

Organismos marinhos como fonte de novos fármacos: histórico & perspectivas

Costa-Lotufo¹,

Wilke²,

Jimenez³

et al. 2009

Quím. Nova

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Recebido em 15/1/09; aceito em 11/3/09; publicado na web em 2/4/09 MARINE ORGANISMS AS A SOURCE OF NEW PHARMACEUTICALS: HISTORY AND PERSPECTIVES. Though sharing only a short part on the natural products timeline, the studies on marine products has already handed in four new drugs to the clinical arsenal and brought up a long and promising list of unique molecules to pre-clinical and clinical trials. Thus, as the available analytical resources improve and the interest of large pharmaceutical companies arises, medical use of marine products has definitely become a reality.Keywords: marine biotechnology; natural products; marine drugs. intrOdUÇÃOOs produtos naturais têm sido a maior fonte de inspiração para diversas áreas da química e da ciência de um modo geral. Usando, copiando ou modificando as moléculas sintetizadas pelos seres vivos, o homem tem obtido inovações para o seu benefício em diversas áreas e, entre elas, a produção de fármacos. Do analgésico morfina, ao antibiótico penicilina, passando pelo anticâncer paclitaxel (Taxol ® ), estima-se que 80% dos fármacos em uso são produtos naturais ou foram inspirados pela natureza.Existem várias revisões recentes que podem ser consultadas para uma visão da contribuição dos produtos naturais na indústria farmacêutica. 1-4 Neste contexto, os organismos terrestres (principalmente micro-organismos e plantas) são os responsáveis por quase a totalidade dessas substâncias, enquanto que os organismos marinhos, apesar de promissores, passaram a ser investigados de maneira sistemática apenas recentemente. Nesta breve revisão comentaremos alguns aspectos históricos dos estudos químicos e farmacológicos realizados com organismos marinhos e suas implicações científicas, como a descoberta de novos produtos naturais com ação em alvos moleculares peculiares, além da utilização desse conhecimento pela indústria farmacêutica no processo de pesquisa e desenvolvimento (P&D) de fármacos.históricO Mares e oceanos ocupam mais de 2/3 da superfície da Terra e abrigam quase todos os grupos de organismos vivos, incluindo representantes de 34 dentre os 36 filos descritos. Sendo assim, os ecossistemas marinhos podem ser considerados como detentores da maior biodiversidade filética, com potencial biotecnológico associado praticamente ilimitado. [5][6][7][8] Até os anos 50, este ecossistema escapou do interesse dos cientistas de produtos naturais, principalmente devido ao difícil acesso às suas profundidades. Com o avanço das técnicas e o advento dos equipamentos seguros de mergulho, na década de 70, algas e invertebrados marinhos puderam dar início às suas histórias nas bancadas dos laboratórios de química e farmacologia. 7 O pesquisador Werner Bergmann da Universidade de Yale (E.U.A.) foi um dos pioneiros, na década de 50, no estudo dos produtos naturais marinhos. Um dos exemplos históricos no desenvolvimento de fármacos marinhos teve origem no seu trabalho de isolamento dos nucleosídeos espongouridina (1) e espongotimidina (2) da esponja Tethya crypta (Cryptotethya crypta). 9 Análogos sintét...

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Total Synthesis of Bryostatin 3

Cited by 157 publications

References 2 publications

Marine Natural Products as Models to Circumvent Multidrug Resistance

Marine Natural Products as Models to Circumvent Multidrug Resistance

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

Organismos marinhos como fonte de novos fármacos: histórico & perspectivas

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