Synthesis of the New Ring System Bispyrido[4',3':4,5]pyrrolo [1,2-a:1',2'-d]pyrazine and Its Deaza Analogue

Parrino, Barbara; Spanò, Virginia; Carbone, Anna; Barraja, Paola; Diana, Patrizia; Cirrincione, Girolamo; Montalbano, Alessandra

doi:10.3390/molecules190913342

Cited by 13 publications

(3 citation statements)

References 30 publications

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“…Pyrrole-fused indoles and related aza-derivatives have emerged as an interesting class of anti-cancer agents endowed with potent activity against different human tumor cell lines and with different mechanisms of action [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. In particular, 8 H -thieno[2,3- b ]pyrrolizinones, also known as “tripentones” ( Chart 1 ), have been shown to demonstrate significant cytotoxicity against tumor cells in the submicro-nanomolar range [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

New Tripentone Analogs with Antiproliferative Activity

et al. 2017

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Tripentones represent an interesting class of compounds due to their significant cytotoxicity against different human tumor cells in the submicro-nanomolar range. New tripentone analogs, in which a pyridine moiety replaces the thiophene ring originating the fused azaindole system endowed with anticancer activity viz 8H-thieno[2,3-b]pyrrolizinones, were efficiently synthesized in four steps with fair overall yields (34–57%). All tripentone derivatives were tested in the range of 0.1–100 μM for cytotoxicity against two human tumor cell lines, HCT-116 (human colorectal carcinoma) and MCF-7 (human breast cancer). The most active derivative, with GI50 values of 4.25 µM and 20.73 µM for HCT-116 and MCF-7 cells, respectively, did not affect the viability of Caco-2 differentiated in normal intestinal-like cells, suggesting tumor cells as the main target of its cytotoxic action. The same compound was further investigated in order to study its mode of action. Results showed that it did not exert necrotic effects, while induced a clear shift of viable cells towards early apoptosis. Flow cytometric analysis demonstrated that this compound caused cell cycle alteration, inhibiting its progression in S and G2/M phases.

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Section: Introductionmentioning

confidence: 99%

New Tripentone Analogs with Antiproliferative Activity

et al. 2017

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“…A few years later from the above-mentioned study, Montalbano et al, with the same reaction conditions, has synthesized various unsymmetrical diketopiperazines 95 with variable yields. Unfortunately, these derivatives exhibited modest cytotoxicity against a panel of 60 human cancer cell lines [ 55 ]. The group of Vigusin and Moody also prepared various pyrazinoindole-1,4-diones as gliotoxin analogues from the reaction of indole-2-carboxylic acid with sarcosine ethyl ester hydrochloride in the presence of EDCI (Scheme not shown).…”

Section: Pyrazinoindol-1-ones B: Synthesis and Biological Propertiesmentioning

confidence: 99%

Synthesis and Biological Activities of Pyrazino[1,2-a]indole and Pyrazino[1,2-a]indol-1-one Derivatives

et al. 2021

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This review concerns the synthesis and biological activities of pyrazino[1,2-a]indoles and pyrazino[1,2-a]indol-1-ones reported since 1997 and the discovery of biological activity of pyrazinoindole derivatives. In the first part, we first presented the synthetic routes that have been reported from a methodological point of view to access the pyrazinoindole unit according to cyclization reactions using or not using metal catalysts. Then, syntheses and neuropsychiatric, auto-immune, anti-infectious and anti-cancer properties of pyrazinoindoles were detailed. In the second part, we first reported the main accesses to pyrazinoindol-1-one substrates according to Michael reactions, metal-catalyzed and metal-free cyclization reactions. The syntheses and anti-cancer, anti-infectious, anti-allergenic and neuropsychiatric properties of pyrazinoindolones were next described and discussed.

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“…The incorporation of heterocyclic rings into pharmaceutical candidates is a major strategy to enhance activity and safety profiles. As a consequence, for a long time, much of our attention has been paid to the design and synthesis of pyrrolo-fused systems. − Several examples in the literature highlighted the indole nucleus as a valuable pharmacophore for potent antimitotic agents, , but less is known about isoindole derivatives. − We have already reported the synthesis of heterocyclic systems in which the isoindole scaffold is condensed with esatomic rings such as a pyrane, pyridine, and pyrimidine , and with a pentatomic one such as pyrazole producing compounds with interesting antitumor activity.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Activity of New [1,2]Oxazolo[5,4-e]isoindole Derivatives in Diffuse Malignant Peritoneal Mesothelioma

et al. 2016

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A series of 22 derivatives of the [1,2]oxazolo[5,4-e]isoindole system were synthesized through an efficient and versatile procedure that involves the annelation of the [1,2]oxazole moiety to the isoindole ring, producing derivatives with a wide substitution pattern. The structure-activity relationship indicates that the N-4-methoxybenzyl group appears crucial for potent activity. In addition, the presence of a 6-phenyl moiety is important and the best activity is reached with a 3,4,5-trimethoxy substituent. The most active compound, bearing both the structural features, was able to inhibit tumor cell proliferation at nanomolar concentrations when tested against the full NCI human tumor cell line panel. Interestingly, this compound was effective in reducing in vitro and in vivo cell growth, impairing cell cycle progression and inducing apoptosis, as a consequence of the inhibition of tubulin polymerization, in experimental models of diffuse malignant peritoneal mesothelioma (DMPM), a rapidly lethal disease, poorly responsive to conventional therapeutic strategies.

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Synthesis of the New Ring System Bispyrido[4',3':4,5]pyrrolo [1,2-a:1',2'-d]pyrazine and Its Deaza Analogue

Cited by 13 publications

References 30 publications

New Tripentone Analogs with Antiproliferative Activity

New Tripentone Analogs with Antiproliferative Activity

Synthesis and Biological Activities of Pyrazino[1,2-a]indole and Pyrazino[1,2-a]indol-1-one Derivatives

Preclinical Activity of New [1,2]Oxazolo[5,4-e]isoindole Derivatives in Diffuse Malignant Peritoneal Mesothelioma

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