New Tripentone Analogs with Antiproliferative Activity

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2017 Nov 22

PMID 29156549

Citations 3

Authors

Barbara Parrino

Salviana Ullo

Alessandro Attanzio

Virginia Spano

Stella Cascioferro

Alessandra Montalbano

Paola Barraja

Luisa Tesoriere

Girolamo Cirrincione

Patrizia Diana

Affiliations

Soon will be listed here.

Abstract

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 8-thieno[2,3-]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 GI 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.

Citing Articles

Cytotoxic Activity of Organotin(IV) Derivatives with Triazolopyrimidine Containing Exocyclic Oxygen Atoms.

Attanzio A, DAgostino S, Busa R, Frazzitta A, Rubino S, Girasolo M Molecules. 2020; 25(4).

PMID: 32075253 PMC: 7070731. DOI: 10.3390/molecules25040859.

New 1,2,4-Oxadiazole Nortopsentin Derivatives with Cytotoxic Activity.

Cascioferro S, Attanzio A, Di Sarno V, Musella S, Tesoriere L, Cirrincione G Mar Drugs. 2019; 17(1).

PMID: 30626057 PMC: 6357034. DOI: 10.3390/md17010035.

New Thiazole Nortopsentin Analogues Inhibit Bacterial Biofilm Formation.

Carbone A, Parrino B, Cusimano M, Spano V, Montalbano A, Barraja P Mar Drugs. 2018; 16(8).

PMID: 30081568 PMC: 6117647. DOI: 10.3390/md16080274.

References

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M . Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2014; 136(5):E359-86. DOI: 10.1002/ijc.29210. View

Carbone A, Parrino B, Barraja P, Spano V, Cirrincione G, Diana P . Synthesis and antiproliferative activity of 2,5-bis(3'-indolyl)pyrroles, analogues of the marine alkaloid nortopsentin. Mar Drugs. 2013; 11(3):643-54. PMC: 3705363. DOI: 10.3390/md11030643. View

Spano V, Pennati M, Parrino B, Carbone A, Montalbano A, Lopergolo A . [1,2]Oxazolo[5,4-e]isoindoles as promising tubulin polymerization inhibitors. Eur J Med Chem. 2016; 124:840-851. DOI: 10.1016/j.ejmech.2016.09.013. View

Lisowski V, Leonce S, Kraus-Berthier L, Sopkova-de Oliveira Santos J, Pierre A, Atassi G . Design, synthesis, and evaluation of novel thienopyrrolizinones as antitubulin agents. J Med Chem. 2004; 47(6):1448-64. DOI: 10.1021/jm030961z. View

Sun D, Lennernas H, Welage L, Barnett J, Landowski C, Foster D . Comparison of human duodenum and Caco-2 gene expression profiles for 12,000 gene sequences tags and correlation with permeability of 26 drugs. Pharm Res. 2002; 19(10):1400-16. DOI: 10.1023/a:1020483911355. View

Parrino B, Carbone A, Ciancimino C, Spano V, Montalbano A, Barraja P . Water-soluble isoindolo[2,1-a]quinoxalin-6-imines: in vitro antiproliferative activity and molecular mechanism(s) of action. Eur J Med Chem. 2015; 94:149-62. DOI: 10.1016/j.ejmech.2015.03.005. View

Spano V, Attanzio A, Cascioferro S, Carbone A, Montalbano A, Barraja P . Synthesis and Antitumor Activity of New Thiazole Nortopsentin Analogs. Mar Drugs. 2016; 14(12). PMC: 5192463. DOI: 10.3390/md14120226. View

Spano V, Parrino B, Carbone A, Montalbano A, Salvador A, Brun P . Pyrazolo[3,4-h]quinolines promising photosensitizing agents in the treatment of cancer. Eur J Med Chem. 2015; 102:334-51. DOI: 10.1016/j.ejmech.2015.08.003. View

Rochais C, Lisowski V, Dallemagne P, Rault S . Synthesis and biological evaluation of novel pyrrolopyrrolizinones as anticancer agents. Bioorg Med Chem. 2006; 14(24):8162-75. DOI: 10.1016/j.bmc.2006.09.022. View

10.

Carbone A, Pennati M, Barraja P, Montalbano A, Parrino B, Spano V . Synthesis and antiproliferative activity of substituted 3[2-(1H-indol-3-yl)- 1,3-thiazol-4-yl]-1H-pyrrolo[3,2-b]pyridines, marine alkaloid nortopsentin analogues. Curr Med Chem. 2013; 21(14):1654-66. DOI: 10.2174/09298673113206660307. View

11.

Rochais C, Duc N, Lescot E, Sopkova-de Oliveira Santos J, Bureau R, Meijer L . Synthesis of new dipyrrolo- and furopyrrolopyrazinones related to tripentones and their biological evaluation as potential kinases (CDKs1-5, GSK-3) inhibitors. Eur J Med Chem. 2008; 44(2):708-16. DOI: 10.1016/j.ejmech.2008.05.011. View

12.

Spano V, Pennati M, Parrino B, Carbone A, Montalbano A, Cilibrasi V . Preclinical Activity of New [1,2]Oxazolo[5,4-e]isoindole Derivatives in Diffuse Malignant Peritoneal Mesothelioma. J Med Chem. 2016; 59(15):7223-38. DOI: 10.1021/acs.jmedchem.6b00777. View

13.

Carbone A, Parrino B, Di Vita G, Attanzio A, Spano V, Montalbano A . Synthesis and antiproliferative activity of thiazolyl-bis-pyrrolo[2,3-b]pyridines and indolyl-thiazolyl-pyrrolo[2,3-c]pyridines, nortopsentin analogues. Mar Drugs. 2015; 13(1):460-92. PMC: 4306947. DOI: 10.3390/md13010460. View

14.

Spano V, Frasson I, Giallombardo D, Doria F, Parrino B, Carbone A . Synthesis and antiproliferative mechanism of action of pyrrolo[3',2':6,7] cyclohepta[1,2-d]pyrimidin-2-amines as singlet oxygen photosensitizers. Eur J Med Chem. 2016; 123:447-461. DOI: 10.1016/j.ejmech.2016.07.051. View

15.

Barraja P, Caracausi L, Diana P, Spano V, Montalbano A, Carbone A . Synthesis and antiproliferative activity of the ring system [1,2]oxazolo[4,5-g]indole. ChemMedChem. 2012; 7(11):1901-4. DOI: 10.1002/cmdc.201200296. View

16.

Rochais C, Cresteil T, Perri V, Jouanne M, Lesnard A, Rault S . MR22388, a novel anti-cancer agent with a strong FLT-3 ITD kinase affinity. Cancer Lett. 2012; 331(1):92-8. DOI: 10.1016/j.canlet.2012.12.017. View

17.

Spano V, Montalbano A, Carbone A, Parrino B, Diana P, Cirrincione G . Synthesis of a new class of pyrrolo[3,4-h]quinazolines with antimitotic activity. Eur J Med Chem. 2014; 74:340-57. DOI: 10.1016/j.ejmech.2013.10.014. View

18.

Parrino B, Carbone A, Di Vita G, Ciancimino C, Attanzio A, Spano V . 3-[4-(1H-indol-3-yl)-1,3-thiazol-2-yl]-1H-pyrrolo[2,3-b]pyridines, nortopsentin analogues with antiproliferative activity. Mar Drugs. 2015; 13(4):1901-24. PMC: 4413193. DOI: 10.3390/md13041901. View

19.

Antoni S, Soerjomataram I, Moller B, Bray F, Ferlay J . An assessment of GLOBOCAN methods for deriving national estimates of cancer incidence. Bull World Health Organ. 2016; 94(3):174-84. PMC: 4773935. DOI: 10.2471/BLT.15.164384. View

20.

Parrino B, Carbone A, Spano V, Montalbano A, Giallombardo D, Barraja P . Aza-isoindolo and isoindolo-azaquinoxaline derivatives with antiproliferative activity. Eur J Med Chem. 2015; 94:367-77. DOI: 10.1016/j.ejmech.2015.03.009. View