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Synthesis and antiproliferative activity of thiazolyl-bis-pyrrolo[2,3-b]pyridines and indolyl-thiazolyl-pyrrolo[2,3-c]pyridines, nortopsentin analogues.

Carbone A, Parrino B, Di Vita G, Attanzio A, Spanò V, Montalbano A, Barraja P, Tesoriere L, Livrea MA, Diana P, Cirrincione G - Mar Drugs (2015)

Bottom Line: A compound of the former series induced apoptosis, evident as externalization of plasma membrane phosphatidylserine (PS), and changes of mitochondrial trans-membrane potential, while blocking the cell cycle in G2/M phase.In contrast, a derivative of the latter series elicited distinct responses in accordance with the dose.Thus, low concentrations (GI30) induced morphological changes characteristic of autophagic death with massive formation of cytoplasmic acid vacuoles without apparent loss of nuclear material, and with arrest of cell cycle at the G1 phase, whereas higher concentrations (GI70) induced apoptosis with arrest of cell cycle at the G1 phase.

View Article: PubMed Central - PubMed

Affiliation: Biological, Chemical and Pharmaceutical Sciences and Technologies Department, STEBICEF, Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Italy. anna.carbone@unipa.it.

ABSTRACT
Two new series of nortopsentin analogues, in which the imidazole ring of the natural product was replaced by thiazole and indole units were both substituted by 7-azaindole moieties or one indole unit was replaced by a 6-azaindole portion, were efficiently synthesized. Compounds belonging to both series inhibited the growth of HCT-116 colorectal cancer cells at low micromolar concentrations, whereas they did not affect the viability of normal-like intestinal cells. A compound of the former series induced apoptosis, evident as externalization of plasma membrane phosphatidylserine (PS), and changes of mitochondrial trans-membrane potential, while blocking the cell cycle in G2/M phase. In contrast, a derivative of the latter series elicited distinct responses in accordance with the dose. Thus, low concentrations (GI30) induced morphological changes characteristic of autophagic death with massive formation of cytoplasmic acid vacuoles without apparent loss of nuclear material, and with arrest of cell cycle at the G1 phase, whereas higher concentrations (GI70) induced apoptosis with arrest of cell cycle at the G1 phase.

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Bis-indolyl alkaloids and analogues.
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marinedrugs-13-00460-f007: Bis-indolyl alkaloids and analogues.

Mentions: The spacer structural profile can vary from a linear chain to carbocycles or heterocycles differently sized. Thus, coscinamides A–C, isolated from deep marine sponge Coscinoderma sp. bearing a linear chain as a spacer, showed HIV inhibitory activity (Chart 1) [17]. Asterriquinone, isolated from Aspergillus fungi, bears a quinone symmetrical structure and showed in vivo activity against Ehrlich carcinoma, ascites hepatoma AH13, and mouse P388 leukemia [18]. Dragmacidins have been isolated from a large number of deep water sponges such as Dragmacidon, Halicortex, Spongosorites, Hexadella and the tunicate Didemnum candidum, and present different spacers and diverse related activities. Dragmacidin and dragmacidins A–C, which exhibit the saturated six-membered heterocyclic link piperazine, showed modest cytotoxic activity [19,20,21]. Instead, a more complex member of this family, dragmacidin D, bearing a pyrazinone moiety as central core, exhibited several biological properties such as inhibition of serine-threonine protein phosphatases, antiviral, antimicrobial, and anticancer activities [22,23].


Synthesis and antiproliferative activity of thiazolyl-bis-pyrrolo[2,3-b]pyridines and indolyl-thiazolyl-pyrrolo[2,3-c]pyridines, nortopsentin analogues.

Carbone A, Parrino B, Di Vita G, Attanzio A, Spanò V, Montalbano A, Barraja P, Tesoriere L, Livrea MA, Diana P, Cirrincione G - Mar Drugs (2015)

Bis-indolyl alkaloids and analogues.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4306947&req=5

marinedrugs-13-00460-f007: Bis-indolyl alkaloids and analogues.
Mentions: The spacer structural profile can vary from a linear chain to carbocycles or heterocycles differently sized. Thus, coscinamides A–C, isolated from deep marine sponge Coscinoderma sp. bearing a linear chain as a spacer, showed HIV inhibitory activity (Chart 1) [17]. Asterriquinone, isolated from Aspergillus fungi, bears a quinone symmetrical structure and showed in vivo activity against Ehrlich carcinoma, ascites hepatoma AH13, and mouse P388 leukemia [18]. Dragmacidins have been isolated from a large number of deep water sponges such as Dragmacidon, Halicortex, Spongosorites, Hexadella and the tunicate Didemnum candidum, and present different spacers and diverse related activities. Dragmacidin and dragmacidins A–C, which exhibit the saturated six-membered heterocyclic link piperazine, showed modest cytotoxic activity [19,20,21]. Instead, a more complex member of this family, dragmacidin D, bearing a pyrazinone moiety as central core, exhibited several biological properties such as inhibition of serine-threonine protein phosphatases, antiviral, antimicrobial, and anticancer activities [22,23].

Bottom Line: A compound of the former series induced apoptosis, evident as externalization of plasma membrane phosphatidylserine (PS), and changes of mitochondrial trans-membrane potential, while blocking the cell cycle in G2/M phase.In contrast, a derivative of the latter series elicited distinct responses in accordance with the dose.Thus, low concentrations (GI30) induced morphological changes characteristic of autophagic death with massive formation of cytoplasmic acid vacuoles without apparent loss of nuclear material, and with arrest of cell cycle at the G1 phase, whereas higher concentrations (GI70) induced apoptosis with arrest of cell cycle at the G1 phase.

View Article: PubMed Central - PubMed

Affiliation: Biological, Chemical and Pharmaceutical Sciences and Technologies Department, STEBICEF, Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Italy. anna.carbone@unipa.it.

ABSTRACT
Two new series of nortopsentin analogues, in which the imidazole ring of the natural product was replaced by thiazole and indole units were both substituted by 7-azaindole moieties or one indole unit was replaced by a 6-azaindole portion, were efficiently synthesized. Compounds belonging to both series inhibited the growth of HCT-116 colorectal cancer cells at low micromolar concentrations, whereas they did not affect the viability of normal-like intestinal cells. A compound of the former series induced apoptosis, evident as externalization of plasma membrane phosphatidylserine (PS), and changes of mitochondrial trans-membrane potential, while blocking the cell cycle in G2/M phase. In contrast, a derivative of the latter series elicited distinct responses in accordance with the dose. Thus, low concentrations (GI30) induced morphological changes characteristic of autophagic death with massive formation of cytoplasmic acid vacuoles without apparent loss of nuclear material, and with arrest of cell cycle at the G1 phase, whereas higher concentrations (GI70) induced apoptosis with arrest of cell cycle at the G1 phase.

Show MeSH
Related in: MedlinePlus