Stereo-specific cytotoxic effects of gossypol enantiomers and gossypolone in tumour cell lines

Shelley, Mike; Hartley, Laura; Fish, R.G.; Groundwater, Paul W.; Morgan, Janet; Mort, D.; Mason, Marsha L.; Evans, Andrew R.

doi:10.1016/s0304-3835(98)00302-4

Cited by 99 publications

(56 citation statements)

References 25 publications

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“…24 In the context of melanoma, gossypol has long been known to kill melanoma cells more efficaciously than normal melanocytes. [25][26][27] However, the mechanism(s) underlying this selectivity is unclear.…”

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confidence: 99%

Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins

et al. 2007

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Melanoma cells depend on sustained proteasomal function for survival. However, bortezomib, the first proteasome inhibitor in clinical use, is not sufficient to improve the poor prognosis of metastatic melanoma patients. Since the proteasome is also expressed in all normal cell compartments, it is unclear how to enhance the efficacy of bortezomib without exacerbating secondary toxicities. Here, we present pharmacological and genetic analyses of mechanisms of resistance to proteasome inhibition. We focused on Bcl-2, Bcl-x L and Mcl-1 as main antiapoptotic factors associated with melanoma progression. Despite an efficient blockage of the proteasome, bortezomib could not counteract the intrinsically high levels of Bcl-2 and Bcl-x L in melanoma cells. Moreover, Mcl-1 was only downregulated at late time points after treatment. Based on these results, a combination treatment including (À)-gossypol, an inhibitor of Mcl-1/Bcl-2/Bcl-x L , was designed and proven effective in vivo. Using a specific RNA interference approach, the survival of bortezomib-treated melanoma cells was found to rely primarily on Mcl-1, and to a lesser extent on Bcl-x L (but not on Bcl-2). Importantly, neither Mcl-1 nor Bcl-x L inactivation affected the viability of normal melanocytes. This hierarchical requirement of Bcl-2 family members for the maintenance of normal and malignant cells offers a therapeutic window to overcome melanoma chemoresistance in a tumor cell-selective manner.

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confidence: 99%

Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins

et al. 2007

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“…Gossypol is toxic to human and animals (Dao et al, 2000;Shelley et al, 1999). Recent reports also showed its anti-cancer, antiviral, spermicidal and antimicrobial activities (Dao et al, 2000;Kim et al, 1984;Yildirim-Aksoy et al, 2004), and of which the ()-gossypol seems to be more active than the (+)-gossypol (Blackstaffe et al, 1997;Shelley et al, 1999;Yildirim-Aksoy et al, 2004).…”

Section: Genetic Engineering Of Gossypol Traitsmentioning

confidence: 99%

“…Recent reports also showed its anti-cancer, antiviral, spermicidal and antimicrobial activities (Dao et al, 2000;Kim et al, 1984;Yildirim-Aksoy et al, 2004), and of which the ()-gossypol seems to be more active than the (+)-gossypol (Blackstaffe et al, 1997;Shelley et al, 1999;Yildirim-Aksoy et al, 2004). Thus the breeding goal towards gossypol traits is expected to increase or maintain the phytoalexins in most organs of cotton plants for high resistance to pests and pathogens, meanwhile to eliminate these compounds in seeds to reduce the usage cost for the high quality edible oil and protein.…”

Section: Genetic Engineering Of Gossypol Traitsmentioning

confidence: 99%

Gossypol: phytoalexin of cotton

Tian

Ruan

Huang

et al. 2016

Sci. China Life Sci.

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Sesquiterpenoids are a class of 15-carbon secondary metabolites that play diverse roles in plant adaptation to environment. Cotton plants accumulate a large amount of sesquiterpene aldehydes (including gossypol) as phytoalexins against pathogens and herbivores. They are stored in pigment glands of aerial organs and in epidermal layers of roots. Several enzymes of gossypol biosynthesis pathway have been characterized, including 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) and farnesyl diphosphate synthase (FPS) that catalyze the formation of the precursor farnesyl diphosphate (FPP), (+)--cadinene synthase (CDN) which is the first enzyme committed to gossypol biosynthesis, and the downstream enzymes of CYP706B1 and methyltransferase. Expressions of these genes are tightly regulated during cotton plants development and induced by jasmonate and fungi elicitors. The transcription factor GaWRKY1 has been shown to be involved in gossypol pathway regulation. Recent development of new genomic platforms and methods and releases of diploid and tetraploid cotton genome sequences will greatly facilitate the elucidation of gossypol biosynthetic pathway and its regulation.cotton, secondary metabolism, gossypol, sesquiterpenoid Citation:

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“…Em geral, o enantiômero (aR)-(-)-gossipol 39 é aquele que apresenta perfil mais pronunciado de bioatividade, quando comparado ao antípoda ótico (aS)-(+)-gossipol 39 e ao racemato correspondente. Neste âmbito, Shelley e colaboradores 48 (Figura 18). A colchicina é um alcalóide tricíclico constituído pela subunidade trimetoxifenila (A), pelo anel de 7 membros contendo o grupo acetamida (B) e pelo sistema tropolônico (C).…”

Section: Efeito Do Atropoisomerismo Em Moléculas Bioativasunclassified

Atropoisomerismo: o efeito da quiralidade axial em substâncias bioativas

Santos¹,

Pinheiro²,

Sodero³

et al. 2007

Quím. Nova

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Recebido em 26/9/05; aceito em 30/3/06; publicado na web em 26/9/06 ATROPISOMERISM: THE EFFECT OF THE AXIAL CHIRALITY IN BIOACTIVE COMPOUNDS. Atropisomerism is a special kind of stereoisomeric relationship that arises from the freezing of a certain conformation of an organic molecule, associated with a high rotational barrier about a single covalent bond. Atropisomerism has been originally described in orto-functionalyzed biphenyl derivatives, but a lot of other organic functionalities can present this structural phenomenon, characterized by the presence of chiral properties in compounds that don't present classical stereogenic centers. Atropisomeric compounds, intermediates and catalysts have well-know importance in organic synthesis, but the influence of the axial chirality in substances able to modulate biological systems is still not very exploited in drug design and development. In this context, the present account describes the importance of this structural property in the medicinal chemistry of different classes of bioactive compounds or therapeutic agents, emphasizing how atropisomerism could affect the molecular recognition of a ligand or a prototype by the target bioreceptor.Keywords: atropisomerism; atropisomerism of drugs; stereoselective molecular recognition. INTRODUÇÃOO fenômeno conhecido como atropoisomerismo, denominação oriunda da palavra grega atropos (i.e. sem rotação), é atribuído a um tipo de estereoisomerismo característico de sistemas onde a rotação livre em torno de uma ligação simples é impedida, produzindo uma barreira energética suficientemente elevada, de modo a permitir o isolamento ou simplesmente a detecção dos diferentes rotâmeros, chamados atropoisômeros 1,2 . Este tipo de isomeria axial é caracterizada pela atividade ótica promovida por um eixo de ligação, não necessitando que a substância apresente carbono estereogênico como elemento de quiralidade. O fenômeno foi observado pela primeira vez por Christie e Kenner 3 , após a resolução dos atropoisômeros do ácido 6,6'-dinitro-2,2'-difênico 1, os quais não se mostraram interconversíveis à temperatura ambiente (Figura 1).A nomenclatura de substâncias que apresentam quiralidade axial pode ser atribuída como R ou S pela aplicação das regras de prioridade de Cahn-Ingold-Prelog 4,5 , conforme exemplificado na Figura 2. A partir da projeção da estrutura vista na direção do eixo de ligação do sistema bifenílico, deve-se definir a ordem de prioridade dos grupos funcionais, iniciando por aqueles mais próximos ao observador e, em seguida, atribuir a configuração absoluta R ou S com base no sentido da rotação produzida quando se caminha do substituinte de maior prioridade para o de menor prioridade. Apesar de ser opcional, a descrição da configuração absoluta de estereoisômeros atropoisoméricos deve ser acompanhada pela introdução do prefixo a, i.e. aR ou aS, visando distinguí-los de outros tipos de compostos oticamente ativos. De maneira alternativa, os compostos atropoisoméricos podem ser vistos como hélices e suas configurações descritas...

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Stereo-specific cytotoxic effects of gossypol enantiomers and gossypolone in tumour cell lines

Cited by 99 publications

References 25 publications

Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins

Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins

Gossypol: phytoalexin of cotton

Atropoisomerismo: o efeito da quiralidade axial em substâncias bioativas

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