Fluorescent 7-diethylaminocoumarin pyrrolobenzodiazepine conjugates: Synthesis, DNA interaction, cytotoxicity and differential cellular localization

Wells, Geoff; Suggitt, Marie; Coffils, Marissa; Baig, Mirza A.H.; Howard, Philip W.; Loadman, Paul M.; Hartley, John A.; Jenkins, Terence C.; Thurston, David E.

doi:10.1016/j.bmcl.2008.01.083

Cited by 27 publications

(14 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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 , . The first type is a dimeric PBD, 74 , with a tripyrrole linker with a TATAA base pairs specificity .…”

Section: Synthetically Produced Pyrrolobenzodiazepinesmentioning

confidence: 99%

“…The length of the linker allows interstrand cross‐linking of DNA that covers roughly one turn of the helix. The second type is the fluorescent 7‐diethylaminocoumarin PBD conjugates 75 , 76 , and 77 (Fig. ).…”

Section: Synthetically Produced Pyrrolobenzodiazepinesmentioning

confidence: 99%

“…Consistent with this analysis, compound 77 , which is only found in the cytoplasm, is the least potent of the three. It is apparent that the cellular distribution of these compounds is a function of the chemical structure of the linker . Lack of uptake in the nucleus could explain the relatively modest cytotoxic activity of 67 compared to its DNA‐binding affinity …”

Section: Antineoplastic Properties Of Pyrrolobenzodiazepinesmentioning

confidence: 99%

“…Two types of hybrid PBDs synthesized by Thurston et al are of particular interest. 116,117 The first type is a dimeric PBD, 74, with a tripyrrole linker with a TATAA base pairs specificity. 116 The length of the linker allows interstrand cross-linking of DNA that covers roughly one turn of the helix.…”

Section: Activities Of Pyrrolobenzodiazepines K 19mentioning

confidence: 99%

See 3 more Smart Citations

Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Gerratana

2010

Medicinal Research Reviews

118

143

View full text Add to dashboard Cite

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.

show abstract

Section: Synthetically Produced Pyrrolobenzodiazepinesmentioning

confidence: 99%

Section: Synthetically Produced Pyrrolobenzodiazepinesmentioning

confidence: 99%

Section: Antineoplastic Properties Of Pyrrolobenzodiazepinesmentioning

confidence: 99%

Section: Activities Of Pyrrolobenzodiazepines K 19mentioning

confidence: 99%

See 2 more Smart Citations

Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Gerratana

2010

Medicinal Research Reviews

118

143

View full text Add to dashboard Cite

show abstract

“…In contrast, the coumarin-PBD conjugate bearing a propylene linker (X= CH 2 ) was the most potent compound (IC 50 values ≤3.2 µM). The biological assessments revealed that the linker structure within these coumarin-PBD conjugates had significant influence on the extent and time course of DNA binding, in vitro cytotoxic potency and cellular distribution [54].…”

Section: A N U S C R I P Tmentioning

confidence: 99%