DNA sequence-selective C8-linked pyrrolobenzodiazepine–heterocyclic polyamide conjugates show anti-tubercular-specific activities

Brucoli, Federico; Guzman, Juan; Basher, Mohammad Anwarul; Evangelopoulos, Dimitrios; McMahon, Eleanor; Munshi, Tulika; McHugh, Timothy D.; Fox, Keith R.; Bhakta, Sanjib

doi:10.1038/ja.2016.43

Cited by 13 publications

(12 citation statements)

References 27 publications

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“…The hybrid compound displayed MIC values of 0.4 or 2.1 μg/mL against drug-sensitive and drug-resistant M. tuberculosis strains, respectively, which is comparable to the MIC values reported for C8-linked PBDs against M. tuberculosis . 20 This is the first report of a nontoxic C8-linked PBD hybrid with activity against M. tuberculosis and is a starting point for the development of nontoxic PBD molecules that do not bind DNA as new antibiotics for TB treatment.…”

Section: Introductionmentioning

confidence: 92%

“…19 C8-linked PBD monomers have shown notable antibacterial activity against MDR Gram-positive bacteria 6,8 and M. tuberculosis . 20 More recently, DNA gyrase inhibition has been reported as an additional mechanism of action of antibacterial PBDs. 6 A study by Brucoli et al evaluated 12 C8-linked PBD-heterocyclic polyamide conjugates for antitubercular activity and DNA sequence selectivity.…”

Section: Introductionmentioning

confidence: 99%

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Noncytotoxic Pyrrolobenzodiazepine–Ciprofloxacin Conjugate with Activity against Mycobacterium tuberculosis

et al. 2019

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The development of new antitubercular agents for the treatment of infections caused by multidrug-resistant (MDR) Mycobacterium tuberculosis is an urgent priority. Pyrrolobenzodiazepines (PBDs) are a promising class of antibacterial agents that were initially discovered and isolated from a range of Streptomyces species. Recently, C8-linked PBD monomers have been shown to work by inhibiting DNA gyrase and have demonstrated activity against M. tuberculosis. However, both PBD monomers and dimers are toxic to eukaryotic cells, limiting their development as antibacterial agents. To eliminate the toxicity associated with PBDs and explore the effect of C8-modification with a known antibacterial agent with the same mechanism of action (i.e., ciprofloxacin, a gyrase inhibitor), we synthesized a C8-linked PBD–ciprofloxacin (PBD–CIP, 3) hybrid. The hybrid compound displayed minimum inhibitory concentration values of 0.4 or 2.1 μg/mL against drug-sensitive and drug-resistant M. tuberculosis strains, respectively. A molecular modeling study showed good interaction of compound 3 with wild-type M. tuberculosis DNA gyrase, suggesting gyrase inhibition as a possible mechanism of action. Compound 3 is a nontoxic combination hybrid that can be utilized as a new scaffold and further optimized to develop new antitubercular agents.

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Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Noncytotoxic Pyrrolobenzodiazepine–Ciprofloxacin Conjugate with Activity against Mycobacterium tuberculosis

et al. 2019

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“…To date, 16 of the PBDs isolated from Streptomyces and Micrococcus were found to have moderate antimicrobial activity [18]. The main reason for this group of compounds gaining importance is the specific binding to the guanine units in the DNA minor groove and being highly effective DNA alkylating agents [19,20]. Thus, some PBD derivatives were shown to be strongly cytotoxic against some cancer cell lines at pM and nM levels (eg.…”

Section: Present Studymentioning

confidence: 99%

Benzodiazepine Derivatives from Marine-Derived Streptomyces cacaoi 14CM034

Aksoy¹,

Küçüksolak²,

Uzel³

et al. 2021

Rec.Nat.Prod.

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7-methoxy-8-hydroxy cycloanthranilylproline (2), a new natural product with pyrrolobenzodiazepine (PBD) framework, was isolated from marine-derived actinobacterium Streptomyces cacaoi 14CM034, together with cycloanthranilylproline (1). Structural elucidation of the compounds was based on FTIR, 1D- (1H and 13C NMR), 2D-NMR (COSY, HMBC and NOESY) and HR-MS analyses. Compounds 1 and 2 exhibited notable antimicrobial activity. The presence of PBD derivatives in S. cacaoi was first demonstrated with this study.

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“…More recent C8-modified PBDs, such as KMR-28-39 (Figure B) synthesized by Rahman and co-workers have demonstrated the evidence of preclinical activity of such PBD conjugates. In addition to their cytotoxicity and anti-tumor activity, PBD-heterocyclic hybrids have shown significant antimicrobial activity. − More recently, PBDs are being used as cytotoxic payloads for antibody–drug conjugates, and a number of these are currently undergoing clinical evaluation …”

Section: Introductionmentioning

confidence: 99%

Effects of Systematic Shortening of Noncovalent C8 Side Chain on the Cytotoxicity and NF-κB Inhibitory Capacity of Pyrrolobenzodiazepines (PBDs)

et al. 2019

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The systematic shortening of the noncovalent element of a C8-linked pyrrolobenzodiazepine (PBD) conjugate ( 13) led to the synthesis of a 19-member library of C8-PBD monomers. The critical elements of 13, which were required to render the molecule cytotoxic, were elucidated by an annexin V assay. The effects of shortening the noncovalent element of the molecule on transcription factor inhibitory capacity were also explored through an enzyme-linked immunosorbent assay-based measurement of nuclear NF-κB upon exposure of JJN-3 cells to the synthesized molecules. Although shortening the noncovalent interactive element of 13 had a less than expected effect upon compound cytotoxicity due to reduced DNA interaction, the transcription factor inhibitory capacity of the molecule was notably altered. This study suggests that a relatively short noncovalent side chain at the C8 position of PBD is sufficient to confer cytotoxicity. The shortened PBD monomers provide a new ADC payload scaffold because of their potent cytotoxicity and druglike properties.

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DNA sequence-selective C8-linked pyrrolobenzodiazepine–heterocyclic polyamide conjugates show anti-tubercular-specific activities

Cited by 13 publications

References 27 publications

Noncytotoxic Pyrrolobenzodiazepine–Ciprofloxacin Conjugate with Activity against Mycobacterium tuberculosis

Noncytotoxic Pyrrolobenzodiazepine–Ciprofloxacin Conjugate with Activity against Mycobacterium tuberculosis

Benzodiazepine Derivatives from Marine-Derived Streptomyces cacaoi 14CM034

Effects of Systematic Shortening of Noncovalent C8 Side Chain on the Cytotoxicity and NF-κB Inhibitory Capacity of Pyrrolobenzodiazepines (PBDs)

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