Synthesis and study of new 4-quinazolinone inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP)

Kulcsár, Gyula; Kálai, Tamás; ErzsebetOsz,; Sár, Cecı́lia P.; Jekő, József; Sümegi, Balázs; Hideg, Kálmán

doi:10.3998/ark.5550190.0004.512

Cited by 17 publications

(3 citation statements)

References 11 publications

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“…20 Although 2-substituted 4(3H)-quinazolinone and 4-substituted 2H-phthalazin-1-one derivatives with nitroxide ring substituents were good antioxidants, these modifications resulted in reduced PARP inhibitory activity. 21 The fact that (1) the biological activity of cyclic nitroxides is highly dependent on substituents borne upon the ring, (2) in preliminary studies 2-(2,2,6,6tetramethyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-benzimidazole-4-carboxamide (4h) reduced the ADP-induced platelet aggre-gation, 22 and (3) the development of a similar PARP inhibitor 2-(1-propyl-4-piperidinyl)-1H-benzimidazol-4-carboxamide (ABT-472) 23 prompted us to synthesize and investigate the 4-carboxamidobenzimidazole series modified with nitroxides and their precursors. Here, we report some structure-activity relationships of these compounds as PARP inhibitors.…”

Section: Introductionmentioning

confidence: 99%

New Poly(ADP-ribose) Polymerase-1 Inhibitors with Antioxidant Activity Based on 4-Carboxamidobenzimidazole-2-ylpyrroline and -tetrahydropyridine Nitroxides and Their Precursors

Kálai

Balog

Szabó³

et al. 2009

J. Med. Chem.

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4-Carboxamidobenzimidazoles were previously described as PARP inhibitor compounds. Here we report upon 4-carboxamido-1H-benzimidazoles substituted in the 2-position with nitroxides or their amine or hydroxylamine precursors. Among the new molecules, a highly active PARP inhibitor 4h (IC(50) = 14 nM) was identified with antioxidant/radical scavenger activity. We concluded that in most cases sterically hindered amines are better PARP inhibitors than their oxidized form and structural changes in the 2-substituted 4-carboxamido-1H-benzimidazoles (such as N-substitution or changing the position of the carboxamide group) were detrimental to PARP inhibition activity but not to antioxidant activity. These results indicate the advantages of combining an antioxidant nitroxide or nitroxide precursor with a PARP inhibitor molecule to decrease or eliminate the deleterious processes initiated by reactive oxygen and reactive nitrogen species (ROS and RNS). The radical scavenging capability of 4h was demonstrated by EPR study of urine collected after drug administration.

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Section: Introductionmentioning

confidence: 99%

New Poly(ADP-ribose) Polymerase-1 Inhibitors with Antioxidant Activity Based on 4-Carboxamidobenzimidazole-2-ylpyrroline and -tetrahydropyridine Nitroxides and Their Precursors

Kálai

Balog

Szabó³

et al. 2009

J. Med. Chem.

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“…SHRs were randomly divided into two groups; SHR-L and SHR-C. SHR-L group was treated with L-2286 (2-[(2-piperidin-1-ylethyl)thio]quinazolin-4(3 H )-one), a water-soluble PARP-inhibitor (5 mg/b.w. in kg/day, n = 12), while SHR-C group received only placebo (n = 11, SHR-C) p. os for 24 weeks [11] , [12] . WKY rats were used as age-matched controls (n = 10).…”

Section: Methodsmentioning

confidence: 99%

PARP-Inhibitor Treatment Prevents Hypertension Induced Cardiac Remodeling by Favorable Modulation of Heat Shock Proteins, Akt-1/GSK-3β and Several PKC Isoforms

et al. 2014

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Spontaneously hypertensive rat (SHR) is a suitable model for studies of the complications of hypertension. It is known that activation of poly(ADP-ribose) polymerase enzyme (PARP) plays an important role in the development of postinfarction as well as long-term hypertension induced heart failure. In this study, we examined whether PARP-inhibitor (L-2286) treatment could prevent the development of hypertensive cardiopathy in SHRs. 6-week-old SHR animals were treated with L-2286 (SHR-L group) or placebo (SHR-C group) for 24 weeks. Wistar-Kyoto rats were used as aged-matched, normotensive controls (WKY group). Echocardiography was performed, brain-derived natriuretic peptide (BNP) activity and blood pressure were determined at the end of the study. We detected the extent of fibrotic areas. The amount of heat-shock proteins (Hsps) and the phosphorylation state of Akt-1Ser473, glycogen synthase kinase (GSK)-3βSer9, forkhead transcription factor (FKHR)Ser256, mitogen activated protein kinases (MAPKs), and protein kinase C (PKC) isoenzymes were monitored. The elevated blood pressure in SHRs was not influenced by PARP-inhibitor treatment. Systolic left ventricular function and BNP activity did not differ among the three groups. L-2286 treatment decreased the marked left ventricular (LV) hypertrophy which was developed in SHRs. Interstitial collagen deposition was also decreased by L-2286 treatment. The phosphorylation of extracellular signal-regulated kinase (ERK)1/2Thr183-Tyr185, Akt-1Ser473, GSK-3βSer9, FKHRSer256, and PKC εSer729 and the level of Hsp90 were increased, while the activity of PKC α/βIIThr638/641, ζ/λ410/403 were mitigated by L-2286 administration. We could detect signs of LV hypertrophy without congestive heart failure in SHR groups. This alteration was prevented by PARP inhibition. Our results suggest that PARP-inhibitor treatment has protective effect already in the early stage of hypertensive myocardial remodeling.

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“…Among these quinazolines, compound (N) produced a high affinity for the inhibition of PARP-1 in mutated carcinoma. Kulcsar et al [22] prepared and evaluated a series of 2-substituted-quinazoline-4-ones as PARP inhibitors (Figure 7). Among these newly synthesized compounds, quinazoline (O), having a tertiary amine linked through an S-ethyl linker at the C-2 position of quinazoline, exhibited potent PARP inhibitory activity.…”

Section: Parp Inhibitorsmentioning

confidence: 99%

Quinazoline Derivatives as Targeted Chemotherapeutic Agents

Zayed

2024

Cureus

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Most of the current chemotherapeutic medications are extremely toxic, exhibit little selectivity, and contribute to the emergence of treatment resistance. Consequently, the discovery of targeted chemotherapy drugs with high selectivity and low side effects is necessary for cancer treatment. The quinazoline system has a broad range and a long history of biological activities. Numerous quinazoline derivatives have been used to treat different types of cancer by working on various molecular targets. This review presents various chemical information, including molecular structure, design, and biological activity of some reported quinazolines that function by inhibiting four types of important molecular targets: dihydrofolate reductase, breast cancer resistant protein, poly-(ADP-ribose)-polymerase, and tubulin polymerization.

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Synthesis and study of new 4-quinazolinone inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP)

Cited by 17 publications

References 11 publications

New Poly(ADP-ribose) Polymerase-1 Inhibitors with Antioxidant Activity Based on 4-Carboxamidobenzimidazole-2-ylpyrroline and -tetrahydropyridine Nitroxides and Their Precursors

New Poly(ADP-ribose) Polymerase-1 Inhibitors with Antioxidant Activity Based on 4-Carboxamidobenzimidazole-2-ylpyrroline and -tetrahydropyridine Nitroxides and Their Precursors

PARP-Inhibitor Treatment Prevents Hypertension Induced Cardiac Remodeling by Favorable Modulation of Heat Shock Proteins, Akt-1/GSK-3β and Several PKC Isoforms

Quinazoline Derivatives as Targeted Chemotherapeutic Agents

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