Natural Products as Leads to Potential Drugs: An Old Process or the New Hope for Drug Discovery?

Newman, David J.

doi:10.1021/jm0704090

Cited by 642 publications

(439 citation statements)

References 78 publications

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“…The first is that, of the antibiotics under clinical development (Table 1), 67% are natural products themselves, or natural product-derived compounds, a percentage perfectly in line with that found with exisiting drugs. 67 The second consideration is that the major players in antibacterial development are small companies, which are not deterred by the small market size for these drugs. However, it should be noted that a significant number of the compounds listed in Table 1 were not discovered by small companies, but actually represent projects abandoned by large pharmaceuticals companies.…”

Section: Future Perspectivesmentioning

confidence: 99%

Antibiotic discovery in the twenty-first century: current trends and future perspectives

Donadio¹,

Maffioli²,

Monciardini³

et al. 2010

J Antibiot

224

126

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New antibiotics are necessary to treat microbial pathogens that are becoming increasingly resistant to available treatment. Despite the medical need, the number of newly approved drugs continues to decline. We offer an overview of the pipeline for new antibiotics at different stages, from compounds in clinical development to newly discovered chemical classes. Consistent with historical data, the majority of antibiotics under clinical development are natural products or derivatives thereof. However, many of them also represent improved variants of marketed compounds, with the consequent risk of being only partially effective against the prevailing resistance mechanisms. In the discovery arena, instead, compounds with promising activities have been obtained from microbial sources and from chemical modification of antibiotic classes other than those in clinical use. Furthermore, new natural product scaffolds have also been discovered by ingenious screening programs. After providing selected examples, we offer our view on the future of antibiotic discovery.

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Section: Future Perspectivesmentioning

confidence: 99%

Antibiotic discovery in the twenty-first century: current trends and future perspectives

Donadio¹,

Maffioli²,

Monciardini³

et al. 2010

J Antibiot

224

126

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“…CPMV-HT transient expression | cytochrome P450 monooxygenase CYP51 family | disease resistance | neofunctionalization | terpenes H igher plants produce a huge array of low molecular weight specialized compounds (natural products) that have important functions in biotic and abiotic stress tolerance (1,2) and that also provide a matchless starting point for drug and agrochemical discovery (3). The cytochrome P450 (P450) superfamily is the largest family of plant metabolic enzymes.…”

mentioning

confidence: 99%

Biochemical analysis of a multifunctional cytochrome P450 (CYP51) enzyme required for synthesis of antimicrobial triterpenes in plants

Geisler

Hughes

Sainsbury

et al. 2013

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

149

134

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Members of the cytochromes P450 superfamily (P450s) catalyze a huge variety of oxidation reactions in microbes and higher organisms. Most P450 families are highly divergent, but in contrast the cytochrome P450 14α-sterol demethylase (CYP51) family is one of the most ancient and conserved, catalyzing sterol 14α-demethylase reactions required for essential sterol synthesis across the fungal, animal, and plant kingdoms. Oats (Avena spp.) produce antimicrobial compounds, avenacins, that provide protection against disease. Avenacins are synthesized from the simple triterpene, β-amyrin. Previously we identified a gene encoding a member of the CYP51 family of cytochromes P450, AsCyp51H10 (also known as Saponin-deficient 2, Sad2), that is required for avenacin synthesis in a forward screen for avenacin-deficient oat mutants. sad2 mutants accumulate β-amyrin, suggesting that they are blocked early in the pathway. Here, using a transient plant expression system, we show that AsCYP51H10 is a multifunctional P450 capable of modifying both the C and D rings of the pentacyclic triterpene scaffold to give 12,13β-epoxy-3β,16β-dihydroxy-oleanane (12,13β-epoxy-16β-hydroxy-β-amyrin). Molecular modeling and docking experiments indicate that C16 hydroxylation is likely to precede C12,13 epoxidation. Our computational modeling, in combination with analysis of a suite of sad2 mutants, provides insights into the unusual catalytic behavior of AsCYP51H10 and its active site mutants. Fungal bioassays show that the C12,13 epoxy group is an important determinant of antifungal activity. Accordingly, the oat AsCYP51H10 enzyme has been recruited from primary metabolism and has acquired a different function compared to other characterized members of the plant CYP51 family-as a multifunctional stereo-and regio-specific hydroxylase in plant specialized metabolism.

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“…The huge structural diversity of natural compounds and their bioactivity potential have meant that several products isolated from plants, marine flora and microorganisms can serve as "lead" compounds for improvement of their therapeutic potential by molecular modification. 2,3 Pterodon genus compromises four species native to Brazil: P. abruptus Benth., P. apparucuri Pedersoli, P. pubescens Benth. (P. emarginatus Vog.)…”

mentioning

confidence: 99%

Furanoditerpenes from Pterodon pubescens benth with selective in vitro anticancer activity for prostate cell line

Spindola¹,

Carvalho²,

Ruiz³

et al. 2009

J. Braz. Chem. Soc.

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O fracionamento biomonitorado do extrato diclorometânico das sementes de Pterodon pubescens Benth forneceu o 6α-acetóxi-7β-hidróxi-vouacapano 1 (inédito), além de quatro diterpenos furânicos (2, 3, 4 e 5). A atividade antiproliferativa dos compostos foi avaliada in vitro contra as linhagens de células tumorais humanas UACC-62 (melanoma), MCF-7 (mama), NCI-H460 (pulmão), OVCAR-03 (ovário), PC-3 (próstata), HT-29 (colon), 786-0 (rim), K562 (leucemia) e NCI-ADR/RES (ovário com fenótipo de resistência a múltiplos fármacos). Os resultados foram expressos em três concentrações efetivas GI 50 (concentração para que ocorra 50% de inibição de crescimento), TGI (concentração que resulta em inibição total de crescimento) e LC 50 (concentração que resulta em 50% de morte celular). A citotoxicidade in vitro foi avaliada também frente a uma linhagem de célula murina normal (3T3). Este é o primeiro relato de atividade anticâncer para os compostos 1, 4 e 5, que apresentaram grande seletividade, dependente da concentração, para PC-3. O composto 1 foi 26 vezes mais potente para inibir 50% do crescimento (GI 50 ) de PC-3, 15 vezes mais citostático (TGI) e 6 vezes menos tóxico (LC 50 ) quando comparado com Doxorrubicina (controle).Activity guided fractionation of Pterodon pubescens Benth. methylene chloride-soluble fraction afforded novel 6α-acetoxi 7β-hydroxy-vouacapan 1 and four known diterpene furans 2, 3, 4, 5. The compounds were evaluated for in vitro cytotoxic activities against human normal cells and tumour cell lines UACC-62 (melanoma), MCF-7 (breast), NCI-H460 (lung, non-small cells), OVCAR-03 (ovarian), PC-3 (prostate), HT-29 (colon), 786-0 (renal), K562 (leukemia) and NCI-ADR/RES (ovarian expressing phenotype multiple drugs resistance). Results were expressed by three concentration dependent parameters GI 50 (concentration that produces 50% growth inhibition), TGI (concentration that produces total growth inhibition or cytostatic effect) and LC 50 (concentration that produces −50% growth, a cytotoxicity parameter). Also, in vitro cytotoxicity was evaluated against 3T3 cell line (mouse embryonic fibroblasts). Antiproliferative properties of compounds 1, 4 and 5 are herein reported for the first time. These compounds showed selectivity in a concentration-dependent way against human PC-3. Compound 1 demonstrated selectivity 26 fold more potent than the positive control, doxorubicin, for PC-3 (prostrate) cell line based on GI 50 values, causing cytostatic effect (TGI value) at a concentration fifteen times less than positive control. Moreover comparison of 50% lethal concentration (LC 50 value) with positive control (doxorubicin) suggested that compound 1 was less toxic.Keywords: Pterodon pubescens, leguminosae, furanoditerpenes, in vitro assay, prostate cell line, cytotoxicity IntoductionThroughout history, natural products have afforded a rich source of compounds that have found many applications in the fields of medicine, pharmacy and biology. Within the sphere of cancer, a number of important new commercialized drugs hav...

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Natural Products as Leads to Potential Drugs: An Old Process or the New Hope for Drug Discovery?

Cited by 642 publications

References 78 publications

Antibiotic discovery in the twenty-first century: current trends and future perspectives

Antibiotic discovery in the twenty-first century: current trends and future perspectives

Biochemical analysis of a multifunctional cytochrome P450 (CYP51) enzyme required for synthesis of antimicrobial triterpenes in plants

Furanoditerpenes from Pterodon pubescens benth with selective in vitro anticancer activity for prostate cell line

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