Identification of novel PARP-1 inhibitors: Drug design, synthesis and biological evaluation

Xie, Zhouling; Zhou, Yiding; Zhao, Wei; He, Jiao; Chen, Yu; Yang, Yong Qing; Li, Zhiyu

doi:10.1016/j.bmcl.2015.08.060

Cited by 19 publications

(9 citation statements)

References 13 publications

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“…Thus, these findings do not support a strong correlation between PARP1-DNA trapping and cytotoxicity of PARPis, which is in contrast with previous reports. 9,10,13 We then took a second strategy to further examine the correlation: Using 2 PARPis simmiparib and talazoparib to treat 4 different human cancer cells including MDA-MB-436 (BRCA1 −/− ), UWB1.289 (BRCA1 −/− ), Capan-1 (BRCA2 −/− ) and HCT-15 (BRCA2 −/− ) that are sensitive to PARPis [5][6][7][8][27][28][29] and detecting their PARP1-DNA trapping. Both PARPis enhanced PARP1-DNA trapping but showed no apparent concentration-dependency in MDA-MB-436, Capan-1 and HCT-15 cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…5,6 However, the results of this approach show a very low correlation with their ability to induce cytotoxicity in HR-deficient cancer cells. 6,13,[27][28][29]38,39 Our analyses also revealed no significant correlation (r = 0.3898; p = 0.4245) between the IC 50 values of 6 known PARPis (olaparib, niraparib, rucaparib, talazoparib, simmiparib and veliparib) in inhibiting the polymerase activity of PARP1 and their respective average IC 50 values in killing 17 PARPi-sensitive cell lines ( Fig. 5e, right; Supporting Information Table 2 [The used IC 50 values for the cell lines except SK-ES-1 and RD-ES were from References 6,13,27 -29,38,39, respectively]).…”

Section: The Dsb Fa Model Serves As a New Molecular Screening Model Fmentioning

confidence: 99%

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Increased PARP1‐DNA binding due to autoPARylation inhibition of PARP1 on DNA rather than PARP1‐DNA trapping is correlated with PARP1 inhibitor's cytotoxicity

Chen

Wang

et al. 2019

Intl Journal of Cancer

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PARP1 inhibitors (PARPis) are used clinically during cancer therapy and are thought to exert their cytotoxicity through PARP1 polymerase inhibition and PARP1‐DNA trapping. Here, we showed no significant correlation between PARP1‐DNA trapping and cytotoxicity induced by PARPis. We complemented PARP1‐knockout sublines with wild‐type PARP1 and 11 mutants with different point mutations that affect the polymerase activity. When examining the PARPi talazoparib, the induced cytotoxicity was highly significantly correlated with cellular PARP1 polymerase activity, but not with its PARP1‐DNA trapping or polymerase inhibition. Similarly, talazoparib's PARP1‐DNA trapping revealed significant correlation with the polymerase activity rather than its inhibition. Differently, however, when evaluating purified wild‐type and mutated PARP1, we identified an almost linear relationship between PARPis’ inhibiting PARP1 dissociation from DNA and their cytotoxicity in 17 cancer cell lines. In contrast, no significant correlation existed between PARP1 polymerase inhibition in the histone‐based systems and the cytotoxicity. After careful comparisons on different methods and detection targets, we conclude that the PARPi‐mediated increase in PARP1‐DNA binding by inhibiting autoPARylation of PARP1 on DNA rather than in PARP1‐DNA trapping is correlated with PARPi's cytotoxicity. Accordingly, we established a new PARPi screening model that more closely predicts cytotoxicity.

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Section: Resultsmentioning

confidence: 99%

Section: The Dsb Fa Model Serves As a New Molecular Screening Model Fmentioning

confidence: 99%

Increased PARP1‐DNA binding due to autoPARylation inhibition of PARP1 on DNA rather than PARP1‐DNA trapping is correlated with PARP1 inhibitor's cytotoxicity

Chen

Wang

et al. 2019

Intl Journal of Cancer

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“…Chemistry As summarized in Table 1, fifteen target compounds ( [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] were synthesized. The synthetic routes are illustrated in Chart 1.…”

Section: Resultsmentioning

confidence: 99%

“…At room temperature, compound 6 reacted with 2-fluoro-5-formylbenzonitrile in tetrahydrofuran for 12 h to obtain intermediate 8, which was then hydrolyzed and cyclized in the presence of hydrazine hydrate and sodium hydroxide solution to obtain 9 with satisfactory yield. Under the protection of nitrogen, compound 9 was treated with oxalochloride to obtain intermediate 10, which was condensed with straight-chain amine containing a benzene ring and then treated with saturated sodium bicarbonate solution to produce the target compounds (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). The structures of all derivatives were characterized by 1 H-and 13 C-NMR spectra and mass spectra (see Supplementary Materials).…”

Section: Resultsmentioning

confidence: 99%

“…[7][8][9] PARP1 protein, a 113 kDa nuclear protein, utilizes C-terminal domain to recognize damaged DNA and binds to broken DNA, thereby facilitating C-terminal domain to decompose oxidized form of nicotinamide adenine dinucleotide (NAD+) into nicotinamide and ADP ribose which further lead to the production of PAR polymers. [10][11][12][13][14] Poly-ADP ribosylated PARP1 promotes the recruitment of DNA repair proteins to the site of SSBs and enables damaged DNA to be repaired by base excision repair. 15,16) PARP2 owns similar function as PARP1, but accounting for 5-10% of total PARP activity.…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis and Activity Evaluation of New Phthalazinone PARP Inhibitors

Huang

Ren

Wang

et al. 2021

CHEMICAL & PHARMACEUTICAL BULLETIN

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Poly(ADP-ribose)polymerase (PARP) is a significant therapeutic target for the treatment of numerous human diseases. Olaparib has been approved as a PARP inhibitor. In this paper, a series of new compounds were designed and synthesized with Olaparib as the lead compound. In order to evaluate the inhibitory activities against PARP1 of the synthesized compounds, in vitro PARP1 inhibition assay and intracellular PARylation assay were conducted. The results showed that the inhibitory activities of the derivatives were related to the type of substituent and the length of alkyl chain connecting the aromatic ring. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT)-based assay also proved that these compounds demonstrating strong inhibition to PARP1 also have high anti-proliferative activities against BRCA2-deficient cell line (Capan-1). Analysis of the entire results suggest that compound 23 with desirable inhibitory efficiency may hold promise for further in vivo exploration of PARP inhibition.

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The Xanthate Route to Indolines, Indoles, and their Aza Congeners

Zard

2020

Chemistry A European J

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Convergentr outes to av ariety of indolines, indoles, oxindoles, and their aza analogues involving radical additions of xanthates are described. Three approaches are summarized. The first is the least general and relies on the generation of aryl or heteroaryl radicals startingf rom diazonium salts. The second involves radical addition to N-allylanilines followed by ring-closure onto the aromatic core. A large varietyo fi ndolines and azaindolines can thus be obtained and, in many cases, converted into the corresponding indoles and azaindoles by variousm ethods. Thes ynthesiso f novel fluoroazaindolines and fluoroazaindoles by ar are homolytic ipso-substitution of fluorine atoms is particularly noteworthy.T he last approachh inges on the direct modification of indoles by radical addition to the pyrrole subunit of the indolen ucleus. Application of this methodology to the total synthesis of melatonin andt he alkaloids mersicarpine, caulerpine, and the pentacyclic skeleton of tronocarpine is briefly discussed. Mosto ft he compounds described herein would be difficult to obtain by more traditional routes.

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Identification of novel PARP-1 inhibitors: Drug design, synthesis and biological evaluation

Cited by 19 publications

References 13 publications

Increased PARP1‐DNA binding due to autoPARylation inhibition of PARP1 on DNA rather than PARP1‐DNA trapping is correlated with PARP1 inhibitor's cytotoxicity

Increased PARP1‐DNA binding due to autoPARylation inhibition of PARP1 on DNA rather than PARP1‐DNA trapping is correlated with PARP1 inhibitor's cytotoxicity

Design, Synthesis and Activity Evaluation of New Phthalazinone PARP Inhibitors

The Xanthate Route to Indolines, Indoles, and their Aza Congeners

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