Highly efficient, practical approach to natural taxol

Denis, Jean‐Noël; Greene, Andrew E.; Guénard, Daniel; Guéritte-Voegelein, Françoise; Mangatal, L.; Pouget, Pierre

doi:10.1021/ja00225a063

Cited by 538 publications

(220 citation statements)

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“…This induces a disruption of the equilibrium within the microtubule system and ultimately leads to cell death Ringel et al, 1991;. Docetaxel has been studied in many murine tumour models, showing activity against subcutaneous (s.c.) B16 melanoma, MX-l mammary cancer, C38 colon carcinoma, CX-1 colon carcinoma, LX-1 lung carcinoma, s.c. early stage pancreatic ductal adenocarcinoma (P03), S.C. colon adenocarcinoma 51 (C51), SK MEL-2 melanoma and OVCAR-3, HOC 8, HOC 10 and HOC 22 ovarian carcinomas (Denis et al, 1988;Bissery et al, 1991;Harrison et al, 1992, Nicoletti et al, 1992. In phase I studies on single-agent docetaxel the major dose-limiting toxicity (DLT) was neutropenia that appeared to be short lasting, dose dependent, schedule independent and non-cumulative (Aapro et al, 1992;Pazdur et al, 1992;Bisset et al, 1993;Burris et al, 1993;Extra et al, 1993;Tomiak et al, 1993).…”

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confidence: 99%

Phase I study on docetaxel and ifosfamide in patients with advanced solid tumours

Pronk

Schrijvers²,

Schellens³

et al. 1998

Br J Cancer

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Summary Docetaxel and ifosfamide have shown significant activity against a variety of solid tumours. This prompted a phase I trial on the combination of these drugs. This phase I study was performed to assess the feasibility of the combination, to determine the maximum tolerated dose (MTD) and the side effects, and to propose a safe schedule for further phase 11 studies. A total of 34 patients with a histologically confirmed solid tumour, who were not pretreated with taxanes or ifosfamide and who had received no more than one line of chemotherapy for advanced disease were entered into the study. Treatment consisted of docetaxel given as a 1-h infusion followed by ifosfamide as a 24-h infusion (schedule A), or ifosfamide followed by docetaxel (schedule B) every 3 weeks. Docetaxel doses ranged from 60 to 85 mg m-2 and ifosfamide doses from 2.5 to 5.0 g m-2. Granulocytopenia grade 3 and 4 were common (89%), short lasting and ifosfamide dose dependent. Febrile neutropenia and sepsis occurred in 17% and 2% of courses respectively. Non-haematological toxicities were mild to moderate and included alopecia, nausea, vomiting, mucositis, diarrhoea, sensory neuropathy, skin and nail toxicity and oedema. There did not appear to be any pharmacokinetic interaction between docetaxel and ifosfamide. One complete response (CR) (soft tissue sarcoma) and two partial responses (PRs) were documented. A dose of 75 mg m-2 of docetaxel combined with 5.0 g m-2 ifosfamide appeared to be manageable. Schedule A was advocated for further treatment.

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confidence: 99%

Phase I study on docetaxel and ifosfamide in patients with advanced solid tumours

Pronk

Schrijvers²,

Schellens³

et al. 1998

Br J Cancer

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“…O potencial que representava o emprego da bacatina III (66) e da desacetil-bacatina III (67) como matéria-prima natural para síntese do taxol (62) foi reconhecido por Potier e colaboradores, entre 1981 e 1984 28 . Em 1988, Greene, Potier e colaboradores 31 , na França, propuseram uma abordagem sintética para a obtenção do taxol (62) a partir da 10-desacetil-bacatina III (67), obtida da folhas de T. baccata. A rota semi-sintética empregada está ilustrada na Figura 13.…”

Section: Fármacos Anti-cancerígenos E Os Produtos Naturaisunclassified

Os produtos naturais e a química medicinal moderna

Viegas¹,

Bolzani²,

Barreiro³

2006

Quím. Nova

175

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Recebido em 10/12/04; aceito em 29/6/05; publicado na web em 20/1/06 THE NATURAL PRODUCTS AND THE MODERN MEDICINAL CHEMISTRY. Natural products have been utilized by humans since ancient times and the relief and cure of their diseases was the first purpose for using natural products in medicine. The history of the oriental and occidental civilizations is very rich in examples of the utilization of natural products in medicine and health care. Chinese traditional medicine is one of the most important examples of how natural products can be efficient in the treatment of diseases, and it points to the importance of scientific research on natural products, concerning the discovery of new active chemical entities. The complexity, chemical diversity and biological properties of natural products always fascinated people, and during the last 200 years, this led to the discovery of important new drugs. In the last 30 years, the development of new bioassay techniques, biotechnology methods, bio-guided phytochemical studies, automated high throughput screening and high performance analytical methods, have introduced new concepts and possibilities of rational drug design and drug discovery. In this context, natural products have played an important and decisive role in the development of modern medicinal chemistry.Keywords: medicinal chemistry; natural products; drug design. INTRODUÇÃOOs produtos naturais são utilizados pela humanidade desde tempos imemoriais. A busca por alívio e cura de doenças pela ingestão de ervas e folhas talvez tenha sido uma das primeiras formas de utilização dos produtos naturais. A história do desenvolvimento das civilizações Oriental e Ocidental é rica em exemplos da utilização de recursos naturais na medicina, no controle de pragas e em mecanismos de defesa, merecendo destaque a civilização Egípcia, Greco-romana e Chinesa. A medicina tradicional chinesa desenvolveu-se com tal grandiosidade e eficiência que até hoje muitas espécies e preparados vegetais medicinais são estudados na busca pelo entendimento de seu mecanismo de ação e no isolamento dos princípios ativos.As técnicas desenvolvidas e utilizadas no Egito para conservação de múmias ainda são um desafio para a Química moderna. Na Idade Antiga, além de técnicas medicinais, muitos venenos foram descobertos na natureza e utilizados para fins de defesa, caça e mesmo ilícitos, como a utilização do veneno de Hemlock (Conium maculatum) na execução de prisioneiros, inclusive Sócrates, durante o Império Grego 1,2 . A natureza sempre despertou no homem um fascínio encantador, não só pelos recursos oferecidos para sua alimentação e manutenção, mas por ser sua principal fonte de inspiração e aprendizado. A busca incessante pela compreensão das leis naturais e o desafio de transpor barreiras à sua sobrevivência, como o clima e as doenças, levaram o homem ao atual estágio de desenvolvimento científico, mesmo após o avanço tecnológico observado nos dias de hoje. BREVE HISTÓRICO DO PAPEL DOS PRODUTOS NATURAIS NA DESCOBERTA DE FÁRMACOSVárias civilizações in...

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“…2. Regioselective silylation of the C7 hydroxyl group [21,22] followed by purification and acetylation [22] afforded the 7-triethylsilyl-10-acetyl derivative 13. In our experience, silylations without purification of 12 [21] were inconsistent and usually gave mixtures from which 13 was difficult to isolate in pure form.…”

Section: Substrates and Reagentsmentioning

confidence: 99%

Specificity of the N-benzoyl transferase responsible for the last step of Taxol biosynthesis

Long

Lagisetti

Coates

et al. 2008

Archives of Biochemistry and Biophysics

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The last few steps in the biosynthesis of the anticancer drug Taxol in yew (Taxus) species are thought to involve the attachment of β-phenylalanine to the C13-O-position of the advanced taxane diterpenoid intermediate baccatin III to yield N-debenzoyl-2′-deoxytaxol, followed by hydroxylation on the side chain at the C2′-position to afford N-debenzoyltaxol, and finally N-benzoylation to complete the pathway. A cDNA encoding the N-benzoyl transferase that catalyzes the terminal step of the reaction sequence was previously isolated from a family of transferase clones (derived from an induced Taxus cell cDNA library) by functional characterization of the corresponding recombinant enzyme using the available surrogate substrate N-debenzoyl-2′-deoxytaxol [Walker et al., Proc. Natl. Acad. Sci. USA 99 (2002) 9166-9171]. Semi-synthetic N-debenzoyltaxol was prepared by coupling of 7-triethylsilybaccatin III and (2R,3S)-β-phenylisoserine protected as the N-Boc N,O-isopropylidene derivative by means of carbodiimide activation and formic acid deprotections. The selectivity of the recombinant N-transferase for N-debenzoyltaxol was evaluated, and the enzyme was shown to prefer, by a catalytic efficiency factor of two, N-debenzoyltaxol over N-debenzoyl-2′-deoxytaxol as the taxoid co-substrate in the benzoyl transfer reaction, consistent with the assembly sequence involving 2′-hydroxylation prior to N-benzoylation. Selectivity for the acyl/ aroyl-CoA co-substrate was also examined, and the enzyme was shown to prefer benzoyl CoA. Transfer from tigloyl-CoA to N-debenzoyltaxol to afford cephalomannine (taxol B) was not observed, nor was transfer observed from hexanoyl-CoA or butanoyl-CoA to yield taxol C or taxol D, respectively. These results support the proposed sequence of reactions for C13-O-side chain assembly in Taxol biosynthesis, and suggest that other N-transferases are responsible for the formation of related, late pathway, N-acylated taxoids.

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Highly efficient, practical approach to natural taxol

Cited by 538 publications

References 1 publication

Phase I study on docetaxel and ifosfamide in patients with advanced solid tumours

Phase I study on docetaxel and ifosfamide in patients with advanced solid tumours

Os produtos naturais e a química medicinal moderna

Specificity of the N-benzoyl transferase responsible for the last step of Taxol biosynthesis

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