BACKGROUND: Ingenol derivatives have received constant and multidisciplinary attention on account of their pleiotropic pattern of biological activity. This includes activation of protein kinase C (PKC), tumour-promotion, anticancer, and anti-HIV properties, and the possibility of dissecting co-cancerogenic and clinically useful activities has been demonstrated. Certain ingenol esters show powerful anticancer activity, and a structure-activity relationship model to discriminate between their apoptotic and non-apoptotic properties has been developed. RESULTS: The polyhydroxylated southern region of ingenol was selectively modified, using the anticancer and PKC activator ingenol 3,20-dibenzoate (IDB) as a lead compound. The evaluation of IDB analogues in apoptosis assays showed strict structure-activity relationships, benzoylation of the 20-hydroxyl being required to trigger apoptosis through a pathway involving caspase-3 and occurring at the specific cell cycle checkpoint that controls the S-M phase transition. Conversely, a study on the activation of the PKC-dependent transcription factors AP-1 and NF-kappaB by IDB analogues showed significant molecular flexibility, including tolerance to changes at the 3- and 20-hydroxyls. IDB-induced apoptosis was independent of activation of PKC, since it was not affected by treatment with the non-isoform-selective PKC inhibitor GF 109230X0. CONCLUSIONS: Remarkable deviations from the tumour-promotion pharmacophore were observed for both the apoptotic and the PKC-activating properties of IDB analogues, showing that ingenol is a viable template to selectively target crucial pathways involved in tumour promotion and development. Since the apoptotic and the PKC-activating properties of ingenoids are mediated by different pathways and governed by distinct structure-activity relationships, it is possible to dissect them by suitable chemical modification. In this context, the esterification pattern of the 5- and 20-hydroxyls is critical.
BACKGROUND:Ingenol derivatives have received constant and multidisciplinary attention on account of their pleiotropic pattern of biological activity. This includes activation of protein kinase C (PKC), tumour-promotion, anticancer, and anti-HIV properties, and the possibility of dissecting co-cancerogenic and clinically useful activities has been demonstrated. Certain ingenol esters show powerful anticancer activity, and a structure-activity relationship model to discriminate between their apoptotic and non-apoptotic properties has been developed. RESULTS: The polyhydroxylated southern region of ingenol was selectively modified, using the anticancer and PKC activator ingenol 3,20-dibenzoate (IDB) as a lead compound. The evaluation of IDB analogues in apoptosis assays showed strict structure-activity relationships, benzoylation of the 20-hydroxyl being required to trigger apoptosis through a pathway involving caspase-3 and occurring at the specific cell cycle checkpoint that controls the S-M phase transition. Conversely, a study on the activation of the PKC-dependent transcription factors AP-1 and NF-kappaB by IDB analogues showed significant molecular flexibility, including tolerance to changes at the 3- and 20-hydroxyls. IDB-induced apoptosis was independent of activation of PKC, since it was not affected by treatment with the non-isoform-selective PKC inhibitor GF 109230X0. CONCLUSIONS: Remarkable deviations from the tumour-promotion pharmacophore were observed for both the apoptotic and the PKC-activating properties of IDB analogues, showing that ingenol is a viable template to selectively target crucial pathways involved in tumour promotion and development. Since the apoptotic and the PKC-activating properties of ingenoids are mediated by different pathways and governed by distinct structure-activity relationships, it is possible to dissect them by suitable chemical modification. In this context, the esterification pattern of the 5- and 20-hydroxyls is critical.
Authors: Adam M Spivak; Alberto Bosque; Alfred H Balch; David Smyth; Laura Martins; Vicente Planelles Journal: Antimicrob Agents Chemother Date: 2015-07-13 Impact factor: 5.191
Authors: Viviane A O Silva; Marcela N Rosa; Olga Martinho; Amilcar Tanuri; João Paulo Lima; Luiz F Pianowski; Rui M Reis Journal: Invest New Drugs Date: 2019-02-01 Impact factor: 3.850
Authors: Celina M Abreu; Sarah L Price; Erin N Shirk; Rodrigo D Cunha; Luiz F Pianowski; Janice E Clements; Amilcar Tanuri; Lucio Gama Journal: PLoS One Date: 2014-05-14 Impact factor: 3.240
Authors: Guochun Jiang; Erica A Mendes; Philipp Kaiser; Daniel P Wong; Yuyang Tang; Ivy Cai; Anne Fenton; Gregory P Melcher; James E K Hildreth; George R Thompson; Joseph K Wong; Satya Dandekar Journal: PLoS Pathog Date: 2015-07-30 Impact factor: 6.823