Synthesis, cytotoxic activity, DNA topoisomerase-II inhibition, molecular modeling and structure–activity relationship of 9-anilinothiazolo[5,4-b]quinoline derivatives

Loza-Mejía, Marco A.; Olvera-Vázquez, Susana; Maldonado-Hernández, Karina; Guadarrama-Salgado, Teresita; González-Sánchez, Ignacio; Rodríguez-Hernández, Fernando; Solano, José D.; Rodríguez‐Sotres, Rogelio; Lira‐Rocha, Alfonso

doi:10.1016/j.bmc.2009.03.052

Cited by 29 publications

(22 citation statements)

References 20 publications

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“…For example, a quinoline ring condensed with an indole moiety led to indoloquinolines ( Figure 1B ), structurally analogous to cryptoleptine, which showed both DNA intercalation and topoisomerase inhibition [10, 11]. Substituted 9-anilinothiazolo[5,4-b]quinolines ( Figure 1B ), which incorporate a quinoline scaffold fused with a thiazole ring, demonstrated cytotoxicity against four cancer cell lines [cervical (HeLa), colorectal (SW480 and SW620), and chronic myelogenous leukemia (K-562)] and also inhibited human topoisomerase II [12]. Annulation of the benzmidazole ring to the quinoline moiety resulted in cyclic benzimidazole[1,2-a]quinolines ( Figure 1B ) with antiproliferative effects on various cancer cells [13].…”

Section: Introductionmentioning

confidence: 99%

IND-2, a pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinoline derivative, circumvents multi-drug resistance and causes apoptosis in colon cancer cells

Karthikeyan

Lee

Moore

et al. 2015

Bioorganic & Medicinal Chemistry

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Naturally occurring condensed quinolines have anticancer properties. In efforts to find active analogues, we designed and synthesized eight polycyclic heterocycles with a pyrimido[1”,2”:1,5]pyrazolo[3,4-b]quinoline framework (IND series). The compounds were evaluated for activity against colon (HCT-116 and S1-MI-80), prostate (PC3 and DU-145), breast (MCF-7 and MDAMB-231), ovarian (ov2008 and A2780), and hepatocellular (HepG2) cancer cells and against non-cancerous Madin Darby canine kidney (MDCK), mouse embryonic fibroblast (NIH/3T3), and human embryonic kidney cells (HEK293). IND-2, a 4-chloro-2-methyl pyrimido[1”,2”:1,5]pyrazolo[3,4-b]quinoline, exhibited more than tenfold selectivity and potent cytotoxic activity against colon cancer cells relative to the other cancer and non-cancer cells. With five additional colon cancer cell lines (HT-29, HCT-15, LS-180, LS-174, and LoVo), IND-2 had similar cytotoxicity and selectivity, and submicromolar concentrations caused changes in the morphology of HCT-116 and HCT-15 cells. IND-2 did not activate the transactivating function of the pregnane X receptor (PXR), indicating that it does not induce PXR-regulated ABCB1 or ABCG2 transporters. Indeed, IND-2 was not a substrate of ABCB1 or ABCG2, and it induced cytotoxicity in HEK293 cells overexpressing ABCB1 or ABCG2 to the same extent as in normal HEK293 cells. IND-2 was cytotoxic to resistant colon carcinoma S1-MI-80 cells, approximately three- and fivefold more than SN-38 and topotecan, respectively. In HCT-116 colon cancer cells, IND-2 produced concentration-dependent changes in mitochondrial membrane potential, leading to apoptosis, and sub-micromolar concentrations caused chromosomal DNA fragmentation. These findings suggest that, by increasing apoptosis, IND-2 has potential therapeutic efficacy for colorectal cancer.

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Section: Introductionmentioning

confidence: 99%

IND-2, a pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinoline derivative, circumvents multi-drug resistance and causes apoptosis in colon cancer cells

Karthikeyan

Lee

Moore

et al. 2015

Bioorganic & Medicinal Chemistry

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“…Unfortunately, no statistically significant correlation with a cross-validation coefficient Q2 > 0.4 was obtained for any QSAR model attempted. It has been reported 17 that DNA/topoisomerase – targeting agents could exhibit useful QSAR correlations using LUMO energy values. Indeed, we found negative LUMO energies for all the compounds in Table 1, indicating that they should be electron acceptors, which could be stabilized by donor DNA base pairs through frontier molecular orbital interactions.…”

Section: Resultsmentioning

confidence: 99%

Structural Simplification of Bioactive Natural Products with Multicomponent Synthesis. 3. Fused Uracil-Containing Heterocycles as Novel Topoisomerase-Targeting Agents

et al. 2011

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After the initial discovery of antiproliferative and apoptosis-inducing properties of a camptothecin-inspired pentacycle based on 1H-indeno[2’,1’:5,6]dihydropyrido[2,3-d]pyrimidine scaffold, a library of its analogues as well as their oxidized planar counterparts were prepared utilizing a practical multicomponent synthetic protocol. The synthesized compounds exhibited submicromolar to low micromolar antiproliferative potencies toward a panel of human cancer cell lines. Biochemical experiments are consistent with the dihydropyridine library members undergoing intracellular oxidation to the corresponding planar pyridines, which then inhibit topoisomerase II activity leading to inhibition of proliferation and cell death. Because of facile synthetic preparation and promising antitopoisomerase activity, both the dihydropyridine and planar pyridine-based compounds represent a convenient starting point for anticancer drug discovery.

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“…For the synthesis and cytotoxic activity of thiazolo [5,4b]quinoline derivatives, see: Rodríguez-Loaiza et al (2004); Loza-Mejía et al (2008, 2009; Adams et al (2002 Hydrogen-bond geometry (Å , ). Symmetry codes: (i) Àx þ 1; Ày þ 1; Àz þ 1; (ii) Àx; Ày þ 1; Àz; (iii) Àx þ 1; Ày þ 1; Àz; (iv) x; y À 1; z.…”

Section: Related Literaturementioning

confidence: 99%

Crystal structure of ethyl 3-anilino-2-{[bis(methylsulfanyl)methylidene]amino}-3-oxopropanoate

2014

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Synthesis, cytotoxic activity, DNA topoisomerase-II inhibition, molecular modeling and structure–activity relationship of 9-anilinothiazolo[5,4-b]quinoline derivatives

Cited by 29 publications

References 20 publications

IND-2, a pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinoline derivative, circumvents multi-drug resistance and causes apoptosis in colon cancer cells

IND-2, a pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinoline derivative, circumvents multi-drug resistance and causes apoptosis in colon cancer cells

Structural Simplification of Bioactive Natural Products with Multicomponent Synthesis. 3. Fused Uracil-Containing Heterocycles as Novel Topoisomerase-Targeting Agents

Crystal structure of ethyl 3-anilino-2-{[bis(methylsulfanyl)methylidene]amino}-3-oxopropanoate

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