Synthetic modified pyrrolo[1,4] benzodiazepine molecules demonstrate selective anticancer activity by targeting the human ligase 1 enzyme: An in silico and in vitro mechanistic study

Shameem, Mohammad; Kumar, Ravi; Krishna, Shagun; Kumar, Ch. Ravi; Siddiqi, Mohammad Imran; Kundu, Bijoy; Banerjee, Dibyendu

doi:10.1016/j.cbi.2015.05.024

Cited by 19 publications

(13 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Since the initial identification of DNA ligase inhibitors by a structure-based approach (18,26), there have been several reports describing LigI inhibitors using computer modelling and derivatives of the original DNA ligase inhibitors (49–51). While these studies have shown that the inhibitors have activity against LigI in vitro, their affinity and selectivity appears to be less than that of L82-G17.…”

Section: Discussionmentioning

confidence: 99%

Structure-activity relationships among DNA ligase inhibitors: Characterization of a selective uncompetitive DNA ligase I inhibitor

et al. 2017

View full text Add to dashboard Cite

In human cells, there are three genes that encode DNA ligase polypeptides with distinct but overlapping functions. Previously small molecule inhibitors of human DNA ligases were identified using a structure-based approach. Three of these inhibitors, L82, a DNA ligase I (LigI)-selective inhibitor, and L67, an inhibitor of LigI and DNA ligases III (LigIII), and L189, an inhibitor of all three human DNA ligases, have related structures that are composed of two 6-member aromatic rings separated by different linkers. Here we have performed a structure-activity analysis to identify determinants of activity and selectivity. The majority of the LigI-selective inhibitors had a pyridazine ring whereas the LigI/III- and LigIII-selective inhibitors did not. In addition, the aromatic rings in LigI-selective inhibitors had either arylhydrazone or acylhydrazone, but not vinyl linkers. Among the LigI-selective inhibitors, L82-G17 exhibited increased activity against and selectivity for LigI compared with L82. Notably. L82-G17 is an uncompetitive inhibitor of the third step of the ligation reaction, phosphodiester bond formation. Cells expressing DNA ligase I were more sensitive to L82-G17 than isogenic LIG1 null cells. Furthermore, cells lacking nuclear LigIIIα, which can substitute for LigI in DNA replication, were also more sensitive to L82-G17 than isogenic parental cells. Together, our results demonstrate that L82-G17 is a LigI-selective inhibitor with utility as a probe of the catalytic activity and cellular functions of LigI and provide a framework for the future design of DNA ligase inhibitors.

show abstract

Section: Discussionmentioning

confidence: 99%

Structure-activity relationships among DNA ligase inhibitors: Characterization of a selective uncompetitive DNA ligase I inhibitor

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Indeed, the tricyclic pyrrolo [1,4]benzodiazepine 1 exhibits a potent inhibition effect on the human DNA ligase (hLig1) [1]. Anticancer activity is also exhibited by the Diazepinomycin 2, a dibenzodiazepine derivative possessing a farnesyl residue and isolated from Micromonospora strain [2].…”

Section: Introductionmentioning

confidence: 99%

“…Anticancer activity is also exhibited by the Diazepinomycin 2, a dibenzodiazepine derivative possessing a farnesyl residue and isolated from Micromonospora strain [2]. Anthramycin 3 and its analogues, on the other hand, are isolated from Streptomyces strains, possess the tricyclic pyrrole [2,1-c] [1,4]benzodiazepine scaffold and exhibit a unique feature-alkylation of the minor groove of DNA. This feature is caused by appropriate geometry and the presence of binding groups such as an imine, a carbinolamine, or a carbinolamine ether group [3].…”

Section: Introductionmentioning

confidence: 99%

“…During our continuous research on the design and synthesis of novel heterocyclic scaffolds and molecules for application in medicinal chemistry-including furo [2,3-d]pyrimidin-2(3H)-one, 3H-pyrrolo [2,3-d]pyrimidin-2(7H)-one, and 5,6-dihydropyrimido [4,5-c]pyridazin-7(8H)-one analogues [4,5], as well as oxazolo [3,2-f ]pyrimidine-5,7-dione derivatives [6]-we designed and developed a novel synthesis method, leading to the fused tricyclic 1,2,3,4-tetrahydrobenzo[e]pyrazino [1,2-a] [1,4]diazepine-6,12(11H, 12aH)-dione 4. This new, liquid-phase approach is complementary to our previously published, solid-phase synthesis of peptide mimetics, but it surpasses the old method in terms of higher yields and process upscaling capabilities [7].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

(S)-2-(4-Chlorobenzoyl)-1,2,3,4-tetrahydrobenzo[e]pyrazino[1,2-a][1,4]diazepine-6,12(11H,12aH)-dione—Synthesis and Crystallographic Studies

Mieczkowski

Trzybiński

Wilczek

et al. 2017

Molbank

View full text Add to dashboard Cite

(S)-2-(4-Chlorobenzoyl)-1,2,3,4-tetrahydrobenzo[e]pyrazino[1,2-a][1,4]diazepine-6,12(11H, 12aH)-dione was obtained in a three-step, one-pot synthesis, starting from optically pure (S)-2-piperazine carboxylic acid dihydrochloride. Selective acylation of the β-nitrogen atom followed by condensation with isatoic anhydride and cyclization with HATU/DIPEA to a seven-member benzodiazepine ring, led to the tricyclic benzodiazepine derivative. Crystallographic studies and initial biological screening were performed for the title compound.

show abstract

“…Dazu zählen sowohl der Bruch von DNA-Strängen [20] sowie die Inhibierung von DNA-Prozessierungsenzymen (z. B. Endonuclease BamH1, [21] RNA-Polymerase [3a, 22] und Ligase 1 [23] ) und spezifischen Transkriptionsfaktoren (z. B. Sp1, [24] NF-Y [25] und NF-kB) [25a, 26] als auch die Regulierung verschiedener Signalwege (z.…”

Section: Introductionunclassified

Entwicklung Pyrrolobenzodiazepin(PBD)‐haltiger Antikörper‐Wirkstoff‐Konjugate (ADCs) ausgehend von Anthramycin

et al. 2016

View full text Add to dashboard Cite

Die Pyrrolo[2,1‐c][1,4]benzodiazepine (PBDs) sind eine Familie sequenzselektiver Wirkstoffe, die an die kleine Furche der DNA binden und eine kovalente Aminalbindung zwischen der C11‐Position und den C2‐NH2‐Gruppen der Guaninbasen bilden. Anthramycin ist das erste Beispiel eines PBD‐Monomers und wurde in den 1960er Jahren entdeckt. In den 1990er Jahren wurde das bekannteste PBD‐Dimer SJG‐136 entwickelt und hat jetzt bereits die klinischen Studien der Phase II in Patienten mit Leukämie und Eierstockkrebs durchlaufen. Seit kurzem werden aus PBD‐Dimeranaloga und spezifisch an Tumorzellen bindenden Antikörpern Antikörper‐Wirkstoff‐Konjugate (ADCs) hergestellt. Von diesen befinden sich derzeit mehrere in klinischen Studien und viele andere in der präklinischen Entwicklung. Dieser Aufsatz zeigt die Entwicklung der PBDs ausgehend von Anthramycin über die ersten PBD‐Dimere bis hin zu PBD‐haltigen ADCs und behandelt sowohl die Struktur‐Wirkungs‐Beziehungen und die Biologie der PBDs als auch die Strategien für ihre Verwendung als Wirkstoffkomponente in ADCs.

show abstract

Synthetic modified pyrrolo[1,4] benzodiazepine molecules demonstrate selective anticancer activity by targeting the human ligase 1 enzyme: An in silico and in vitro mechanistic study

Cited by 19 publications

References 37 publications

Structure-activity relationships among DNA ligase inhibitors: Characterization of a selective uncompetitive DNA ligase I inhibitor

Structure-activity relationships among DNA ligase inhibitors: Characterization of a selective uncompetitive DNA ligase I inhibitor

(S)-2-(4-Chlorobenzoyl)-1,2,3,4-tetrahydrobenzo[e]pyrazino[1,2-a][1,4]diazepine-6,12(11H,12aH)-dione—Synthesis and Crystallographic Studies

Entwicklung Pyrrolobenzodiazepin(PBD)‐haltiger Antikörper‐Wirkstoff‐Konjugate (ADCs) ausgehend von Anthramycin

Contact Info

Product

Resources

About