Recent Advances in the Solid-Phase Combinatorial Synthetic Strategies for the Benzodiazepine Based Privileged Structures

Kamal, Ähmed; Reddy, K. Laxma; Devaiah, V.; Shankaraiah, Nagula; Reddy, D. Rajasekhar

doi:10.2174/138955706775197875

Cited by 58 publications

(29 citation statements)

References 55 publications

(104 reference statements)

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“…These compounds are minor groove sequence‐specific DNA alkylating agents with remarkable potency against cancer cells, and are the subject of this review. Excellent reviews have recently covered advances in the synthesis of PBDs , . Hence, we report only on significantly bioactive synthetic PBDs as well as recently synthesized PBDs not covered by the above‐mentioned review.…”

Section: Introductionmentioning

confidence: 99%

“…Excellent reviews have recently covered advances in the synthesis of PBDs. 12,[14][15][16] Hence, we report only on significantly bioactive synthetic PBDs as well as recently synthesized PBDs not covered by the above-mentioned review. The main focus of this review is on recent discoveries in the biosynthesis of naturally produced PBDs and on the biological activities of these compounds.…”

Section: Introductionmentioning

confidence: 99%

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Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Gerratana

2010

Medicinal Research Reviews

118

143

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Pyrrolobenzodiazepines (PBDs) are sequence selective DNA alkylating agents with remarkable antineoplastic activity. They are either naturally produced by actinomycetes or synthetically produced. The remarkable broad spectrum of activities of the naturally produced PBDs encouraged the synthesis of several PBDs, including dimeric and hybrid PBDs yielding to an improvement in the DNA binding sequence specificity and in the potency of this class of compounds. However, limitation in the chemical synthesis prevented the testing of one of the most potent PBDs, sibiromycin, a naturally produced glycosylated PBDs. Only recently the biosynthetic gene clusters for PBDs have been identified opening the doors to the production of glycosylated PBDs by mutasynthesis and biosynthetic engineering. The present review describes the recent studies on the biosynthesis of naturally produced pyrrolobenzodiazepines. In addition, it provides an overview on the isolation and characterization of naturally produced PBDs, on the chemical synthesis of PBDs, on the mechanism of DNA alkylation, and on the DNA binding affinity and cytotoxic properties of both naturally produced and synthetic pyrrolobenzodiazepines.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Gerratana

2010

Medicinal Research Reviews

118

143

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“…Interestingly, the first literature evidence of benzo [1,4]diazepine solid-phase synthesis occurred in 1977 (www.espatentes.com/pdf/0445831_A1.pdf), only twelve years after Merrifield's introduction of solid-phase peptide synthesis [11] and almost twenty years before the beginning of the solid-phase heterocyclic era. In 2006, the preparation of benzodiazepines was reviewed by Kamal [12] and was partially addressed in several other review articles [13,14]. The following section summarizes all strategies reported to date.…”

Section: Introductionmentioning

confidence: 99%

Solid-Phase Synthesis of Seven-Membered Heterocycles with Two Nitrogen Atoms

Fülöpová

Soural

2017

Topics in Heterocyclic Chemistry

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Due to the importance of diazepines and diazepanes in medicinal chemistry and chemical biology, their preparation from diverse starting materials has been frequently reported. In this chapter, we summarize all strategies employing the method of solid-phase synthesis. More than seventeen different types of target compounds are accessible. The individual approaches are grouped according to the type of the target scaffold.

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“…The pyrrolo[2,1- c ][1,4] benzodiazepines (PBDs) are a group of sequence-selective DNA minor-groove binding agents originally discovered in Streptomyces species [1], [2], [3], [4], [5]. Anthramycin ( 1 , Figure 1 ) was the first PBD to be isolated and studied [6], although more than twelve naturally occurring PBDs are now known [1].…”

Section: Introductionmentioning

confidence: 99%

Pyrrolobenzodiazepines (PBDs) Do Not Bind to DNA G-Quadruplexes

et al. 2014

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The pyrrolo[2,1-c][1,4] benzodiazepines (PBDs) are a family of sequence-selective, minor-groove binding DNA-interactive agents that covalently attach to guanine residues. A recent publication in this journal (Raju et al, PloS One, 2012, 7, 4, e35920) reported that two PBD molecules were observed to bind with high affinity to the telomeric quadruplex of Tetrahymena glaucoma based on Electrospray Ionisation Mass Spectrometry (ESI-MS), Circular Dichroism, UV-Visible and Fluorescence spectroscopy data. This was a surprising result given the close 3-dimensional shape match between the structure of all PBD molecules and the minor groove of duplex DNA, and the completely different 3-dimensional structure of quadruplex DNA. Therefore, we evaluated the interaction of eight PBD molecules of diverse structure with a range of parallel, antiparallel and mixed DNA quadruplexes using DNA Thermal Denaturation, Circular Dichroism and Molecular Dynamics Simulations. Those PBD molecules without large C8-substitutents had an insignificant affinity for the eight quadruplex types, although those with large π-system-containing C8-substituents (as with the compounds evaluated by Raju and co-workers) were found to interact to some extent. Our molecular dynamics simulations support the likelihood that molecules of this type, including those examined by Raju and co-workers, interact with quadruplex DNA through their C8-substituents rather than the PBD moiety itself. It is important for the literature to be clear on this matter, as the mechanism of action of these agents will be under close scrutiny in the near future due to the growing number of PBD-based agents entering the clinic as both single-agents and as components of antibody-drug conjugates (ADCs).

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Recent Advances in the Solid-Phase Combinatorial Synthetic Strategies for the Benzodiazepine Based Privileged Structures

Cited by 58 publications

References 55 publications

Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Solid-Phase Synthesis of Seven-Membered Heterocycles with Two Nitrogen Atoms

Pyrrolobenzodiazepines (PBDs) Do Not Bind to DNA G-Quadruplexes

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