Progress in the Discovery of Biosynthetic Anticancer Drugs

Pettit, George R.

doi:10.1021/np9604386

Cited by 152 publications

(110 citation statements)

References 122 publications

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“…These macrocycles subsequently have been identified as important leads in cancer chemotherapy, and bryostatin 1 recently has entered phase II human clinical trials for the treatment of melanoma, non-Hodgkins lymphoma, and renal cancer (current information on bryostatin clinical trials can be found on the Web at: http:͞͞cancernet.nci.nih.gov͞ prot͞protsrch.shtml). This compound continues to be evaluated in phase I clinical trials, alone and in combination with other drugs, for the treatment of other types of cancer (2). Adding to the interest in the bryostatins is their unique biochemistry.…”

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confidence: 99%

“…The initial isolation of bryostatin 1 from B. neritina, for example, required 500 kg of wet animals (1, 2) to obtain sufficient material for structural characterization and bioassay. Subsequent isolations of this and other bryostatins have produced yields ranging from 10 Ϫ3 to 10 Ϫ8 % (2). In an effort to generate adequate material for human therapeutic use, large-scale aquaculture of B. neritina currently is being investigated (6).…”

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confidence: 99%

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The design, computer modeling, solution structure, and biological evaluation of synthetic analogs of bryostatin 1

Wender

Debrabander

Harran

et al. 1998

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

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107

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The bryostatins are a unique family of emerging cancer chemotherapeutic candidates isolated from marine bryozoa. Although the biochemical basis for their therapeutic activity is not known, these macrolactones exhibit high affinities for protein kinase C (PKC) isozymes, compete for the phorbol ester binding site on PKC, and stimulate kinase activity in vitro and in vivo. Unlike the phorbol esters, they are not first-stage tumor promoters. The design, computer modeling, NMR solution structure, PKC binding, and functional assays of a unique class of synthetic bryostatin analogs are described. These analogs (7b, 7c, and 8) retain the putative recognition domain of the bryostatins but are simplified through deletions and modifications in the C4-C14 spacer domain. Computer modeling of an analog prototype (7a) indicates that it exists preferentially in two distinct conformational classes, one in close agreement with the crystal structure of bryostatin 1. The solution structure of synthetic analog 7c was determined by NMR spectroscopy and found to be very similar to the previously reported structures of bryostatins 1 and 10. Analogs 7b, 7c, and 8 bound strongly to PKC isozymes with K i ‫؍‬ 297, 3.4, and 8.3 nM, respectively. Control 7d, like the corresponding bryostatin derivative, exhibited weak PKC affinity, as did the derivative, 9, lacking the spacer domain. Like bryostatin, acetal 7c exhibited significant levels of in vitro growth inhibitory activity (1.8-170 ng͞ml) against several human cancer cell lines, providing an important step toward the development of simplified, synthetically accessible analogs of the bryostatins.

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confidence: 99%

mentioning

confidence: 99%

The design, computer modeling, solution structure, and biological evaluation of synthetic analogs of bryostatin 1

Wender

Debrabander

Harran

et al. 1998

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

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107

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“…Although triterpenes and flavonoids have been described in the literature as inhibitors of human lymphocytes proliferation (Moiteiro et al, 2001;Brochado et al, 2003;Arokiyaraj et al, 2007), the action of these compounds appears to be inhibited by other compounds with immunostimulating effects, such as alkaloids (Sheng, Bryngelsson, Pero, 2000), since the results obtained showed an increase in cell proliferation and possibly activation of T lymphocytes. Given the finding of the stimulating lymphocyte response and that the literature describes the betulinic acid, also present in this species, as a promising anticancer agent against melanoma by inhibiting the growth of cancer cells and inducing apoptosis (Pettit, 1996), the continuity of studies with fractions and isolated compounds of this plant can contribute to advances in the field of immunotherapy.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of the proliferative activity of methanol extracts from six medicinal plants in murine spleen cells

Zandonai

Coelho

Ferreira

et al. 2010

Braz. J. Pharm. Sci.

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A number of natural compounds have been used as immunomodulatory agents, enabling the function of the immune system to be modified by stimulating or suppressing it. There has been increasing interest in the study of therapeutic action of plant extracts regarding their immunomodulatory activity. The aim of this study was to identify and evaluate the action of extracts of the medicinal plants Calophyllum brasiliense, Ipomoea pes-caprae, Matayba elaeagnoides, Maytenus robusta, Rubus imperialis and Vernonia scorpioides on the development of spleen cells from mice, using the in vitro cellular proliferation assay. The cells, obtained by mechanical rupture of mice spleen (5x10 4 cells/mL), were incubated with methanol extracts (10, 50, 100 and 200 mg/mL) and phytohemagglutinin (PHA, 5 mg/mL). The basal control for proliferation consisted of cells alone, while the positive control consisted of cells and PHA. The cell culture was kept at 37 o C in 5% CO 2 for 72 hours, and cell proliferation was revealed by the blue tetrazolium reduction assay (MTT). The results were expressed as percentage of growth and were analyzed using the Kruskal-Wallis and Mann-Whitney tests. The C. brasiliense, I. pes-caprae and M. elaeagnoides extracts showed dose-dependent induction of cell proliferation, with a significant increase in cell proliferation (p<0.03) and percentage growth of 88.2%, 73.1% and 52.7%, respectively, suggesting T lymphocyte stimulation. By contrast, M. robusta, R. imperialis and V. scorpioides extracts showed significance only with a negative percentage of growth, suggesting inhibition of cell proliferation (p<0.04). Further biomonitoring studies will enable the fractions and isolated substances responsible for the immunomodulatory activities to be identified. Várias substâncias de origem natural têm sido utilizadas como agentes imunomoduladores, permitindo modificar a função do sistema imune e propiciando o estudo de atividades terapêuticas de extratos de plantas. Este trabalho objetivou identificar a atividade imunomodulatória dos extratos de seis plantas medicinais da flora brasileira, Calophyllum brasiliense, Ipomoea pes-caprae, Matayba elaeagnoides, Maytenus robusta, Rubus imperialis e Vernonia scorpioides, sobre a proliferação de células esplênicas de camundongos. As células esplênicas murinas obtidas por ruptura mecânica do baço (5x14 3 células/mL) foram incubadas com os extratos metanólicos das plantas (10, 50, 100, 200 mg/mL) e fito-hemaglutinina (PHA, 5 mg/mL). O controle basal de proliferação foi constituído de células apenas e o controle positivo formado por células e PHA. O cultivo celular foi mantido a 37 o C, 5% de CO 2 , 72 horas, com quantificação da proliferação celular pelo ensaio de redução do azul de tetrazólio. Os resultados expressos em percentagem de crescimento foram analisados pelos testes de Kruskal-Wallis e Mann-Whitney. Os extratos de C. brasiliense, I. pes-caprae e M. elaeagnoides mostraram indução dose-dependente da proliferação celular (p<0,03), com percentagem de crescimento de, respecti...

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“…La dolastatine 10 est un inhibiteur non compétitif de l'assemblage des microtubules, qui agit au niveau du site de liaison des vinca-alcaloïdes. Elle favorise et stabilise la liaison de la colchicine avec la tubuline [18]. Quatre essais cliniques de phase I et onze essais de phase II ont été réalisés avec la dolastatine 10, et plusieurs dérivés sont en cours de développement.…”

Section: Les Bryostatinesunclassified