Development of Pyrrolo[2,1‐<i>c</i>][1,4]benzodiazepine β‐Galactoside Prodrugs for Selective Therapy of Cancer by ADEPT and PMT

Kamal, Ähmed; Tekumalla, Venkatesh; Krishnan, Anita; Pal‐Bhadra, Manika; Bhadra, Utpal

doi:10.1002/cmdc.200700328

Cited by 36 publications

(9 citation statements)

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“…Kamal and co‐workers have recently synthesized the monomeric and dimeric β‐glucuronide prodrugs (Fig. ), encouraged by the efficient activation by E. coli β‐galactosidase of a previously produced monomeric PBD β‐galactoside prodrug and on the high level of expression of β‐glucuronidase in solid tumors compared to healthy tissues . Both monomeric and dimeric glucuronide prodrugs are efficiently cleaved in vitro by E. coli β‐glucuronidase (Fig.…”

Section: Synthetically Produced Pyrrolobenzodiazepinesmentioning

confidence: 99%

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%

Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Gerratana

2010

Medicinal Research Reviews

118

143

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“…Branching of biologically active compounds with mono saccharides and disaccharides has been utilized to enhance their water solubility, cellular intake, and consequently modulate their pharmacological characteristics . In view of that, the 2‐ONN derivatives 7 was glycosylated with three glycosyl bromides under basic conditions (Table ).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Biological Evaluation of Glycosides and Acyclic Nucleosides Derived 2‐Oxonicotinonitriles

Mohammed

Abou‐Elkhair

Moustafa

2019

Journal of Heterocyclic Chem

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Synthesis and biological evaluations of a series of 2‐oxonicotinonitriles (2‐ONNs) derivatives are described. Incorporation of branching and solubilizing groups to the 2‐ONN derivative 7 was attained by coupling with several organo‐halides/alkylating agents including three glycosyl bromides under basic conditions. Coupling of 2‐ONNs occurred mainly at the ring nitrogen position and to a lesser extent at the 2‐oxo position giving the O‐alkylated products. Alkylated ONNs and free nucleosides/glycosides derived from the 2‐ONN derivative 7 were tested for their antibacterial, antifungal, and antiviral activities. N‐propargyl and N‐allyl derivatives 23 and 25 showed significant anti‐SARS‐CoV. The N‐butylacetate and O‐allyl derivatives 18 and 26 showed potent antibacterial activities against both Gram‐positive (Staphylococcus aureus, Micrococci luteus) and Gram‐negative (Pseudomonas aeruginosa, Escherichia coli) bacterial strains. The N‐glucoside derivative 8 showed significant antifungal activity.

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“…In order to improve their selectivity towards cancer tissues, -galactoside prodrugs have been synthesized and their selective anticancer activity has been demonstrated in vitro. Furthermore, their enhanced water solubility and stability, as compared to the parent moieties, enormously improves their prospect as new drugs for cancer treatment [51]. Consistently, the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA) [52], and different nitric oxide donors [53] conjugated to D-galactose have been evaluated for selective cancer chemotherapy, both in PMT and in ADEPT strategies.…”

Section: Cancermentioning

confidence: 99%

“…Different approaches can be used for the synthesis of a galactosidic bind between the 1' hydroxyl group of the sugar and a hydroxyl group of the parent drug. The commercially available acetobromo--galactose allows a nucleophilic substitution for the preparation of -galactosidic prodrugs [44,51]. Cleavage of acetyl groups is obtained with sodium methoxide in anhydrous methanol Fig.…”

Section: Synthetic Strategiesmentioning

confidence: 99%

D-Galactose as a Vector for Prodrug Design

Melisi¹,

Curcio²,

Luongo³

et al. 2011

CTMC

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D-galactose is a simple and natural compound that has mainly been exploited in prodrug strategies. Galactosyl prodrugs can be considered a good approach to reach different goals in clinical drug application, especially when traditional drugs are likely to fail therapeutically owing to reasons such as the lack of site specificity, toxicity, and chemical instability. Indeed, of paramount importance is their ability to increase the selectivity of the parent compound, a phenomenon that helps to reduce the incidence of adverse effects, while preserving intact the pharmacodynamic features of the parent drug. Study results have varied according to the type of linkage between the drug and the hydroxyl group exploited. By working with these parameters, researchers have been able not only to generate selective pharmacological targeting of brain, liver, and cancerous cells, but also to improve cellular permeability as well as the pharmacokinetic profile of parent drugs. This review describes the broad spectrum of possibilities for exploiting D-galactose as a vector for prodrug design and the synthetic strategies that allow its realization.

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Development of Pyrrolo[2,1‐c][1,4]benzodiazepine β‐Galactoside Prodrugs for Selective Therapy of Cancer by ADEPT and PMT

Cited by 36 publications

References 50 publications

Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Synthesis and Biological Evaluation of Glycosides and Acyclic Nucleosides Derived 2‐Oxonicotinonitriles

D-Galactose as a Vector for Prodrug Design

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