Phosphonate-linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates: Synthesis, DNA-binding affinity and cytotoxicity

Kamal, Ähmed; Kumar, Praveen; Seshadri, B. N.; Srinivas, O.; Kumar, Manvendra; Sen, Subrata; Kurian, Nisha; Juvekar, Aarti; Zingde, Surekha M.

doi:10.1016/j.bmc.2008.01.040

Cited by 18 publications

(4 citation statements)

References 29 publications

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“…Additionally, the chromophoric properties of these moieties allowed a detailed study of their binding mode to DNA, discussed in Section . Diethylphosphonate ( 69 ), triazolebenzothiadiazine ( 70 ), indole ( 71 ),, and enediyne ( 72 , 73 ) conjugates were synthesized to increase cytotoxicity and in some cases solubility. Two types of hybrid PBDs synthesized by Thurston et al are of particular interest , .…”

Section: Synthetically Produced Pyrrolobenzodiazepinesmentioning

confidence: 99%

“…However, the C2‐difluoro modification has an even more deleterious effect, as shown by the very good GI 50 average value for 61 compared to those of 62 (Table ). Among the phosphonate PBD conjugates, only compound 69 with n =3 and m =1 displays significant cytotoxic activity especially for myeloma …”

Section: Antineoplastic Properties Of Pyrrolobenzodiazepinesmentioning

confidence: 99%

“…Chemical syntheses of naturally occurring PBDs, such as anthramycin, DC‐81, tomaymycin, and chicaymycin have been reported. More than 60 not naturally occurring monomeric PBDs have been synthesized,, as shown in Figures and . Chemical synthesis of naturally occurring PBDs and their analogs is hampered by the stability of the N10‐C11 imine bond, retention of stereochemistry at C11a, loss of unsaturation in the C‐ring under reductive cyclization, and dependency on ring A substituents for the diazepine ring closure , .…”

Section: Synthetically Produced Pyrrolobenzodiazepinesmentioning

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: Synthetically Produced Pyrrolobenzodiazepinesmentioning

confidence: 99%

Section: Antineoplastic Properties Of Pyrrolobenzodiazepinesmentioning

confidence: 99%

Section: Synthetically Produced Pyrrolobenzodiazepinesmentioning

confidence: 99%

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Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Gerratana

2010

Medicinal Research Reviews

118

143

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“…15 Earlier the RED 100 assay was used to find the DNA-binding ability of benzothiadiazine-PBDs and phosphonate linked-PBD conjugates. 16,17 Furthermore, the same technique was used to study the covalent DNA interaction of the PBD dimers and to distinguish the monomeric and dimeric families. 18 Preincubation of PBD molecules with DNA leads to the formation of the DNA-drug complex.…”

Section: Biologymentioning

confidence: 99%

Synthesis, DNA binding affinity and anticancer activity of novel 4H-benzo[g][1,2,3]triazolo[5,1-c][1,4]oxazocines

et al. 2016

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A new class of tricyclic heterocycles 4H-benzo[g][1,2,3]triazolo[5,1-c][1,4]oxazocines was synthesized through a Knoevenagel condensation/azide-alkyne cycloaddition reaction cascade in one-pot operation. These eight membered ring containing heterocycles exhibited moderately high anticancer activity against four cancer cell lines; human cervix cancer cell line (HeLa), human prostate cancer cell line (DU145), human breast cancer cell line (MCF-7) and human breast adenocarcinoma epithelial cell line (MDA-MB-231). Our results indicate that these compounds have a weak cytotoxic effect on normal human mammary epithelial cell line (MCF-10A). Cell cycle and apoptosis assay indicate that they inhibit the cell cycle at the G2/M phase and induce apoptosis. Through the RED assay, it is evident that they have potential to inhibit pBR 322 plasmid DNA cleavage by BamH1. UV-visible, fluorescence titration and viscosity studies suggested that these compounds possess DNA binding affinity.

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Benzodiazepines

2018

Privileged Structures in Drug Discovery

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Phosphonate-linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates: Synthesis, DNA-binding affinity and cytotoxicity

Cited by 18 publications

References 29 publications

Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Synthesis, DNA binding affinity and anticancer activity of novel 4H-benzo[g][1,2,3]triazolo[5,1-c][1,4]oxazocines

Benzodiazepines

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