PMID: 11262084Mar 23, 2001Paper

Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine DNA-interactive agent with highly efficient cross-linking ability and potent cytotoxicity

Journal of Medicinal Chemistry
Stephen J GregsonDavid E Thurston

Abstract

A novel sequence-selective pyrrolobenzodiazepine (PBD) dimer 5 (SJG-136) has been developed that comprises two C2-exo-methylene-substituted DC-81 (3) subunits tethered through their C8 positions via an inert propanedioxy linker. This symmetric molecule is a highly efficient minor groove interstrand DNA cross-linking agent (XL(50) = 0.045 microM) that is 440-fold more potent than melphalan. Thermal denaturation studies show that, after 18 h incubation with calf thymus DNA at a 5:1 DNA/ligand ratio, it increases the T(m) value by 33.6 degrees C, the highest value so far recorded in this assay. The analogous dimer 4 (DSB-120) that lacks substitution/unsaturation at the C2 position elevates melting by only 15.1 degrees C under the same conditions, illustrating the effect of introducing C2-exo-unsaturation which serves to flatten the C-rings and achieve a superior isohelical fit within the DNA minor groove. This behavior is supported by molecular modeling studies which indicate that (i) the PBD units are covalently bonded to guanines on opposite strands to form a cross-link, (ii) 5 has a greater binding energy compared to 4, and (iii) 4 and 5 have equivalent binding sites that span six base pairs. Dimer 5 is significantly more cytot...Continue Reading

References

Dec 20, 1983·Nucleic Acids Research·G ManziniF Quadrifoglio
Nov 15, 1996·The Journal of Organic Chemistry·David E. ThurstonLaurence H. Hurley

❮ Previous
Next ❯

Citations

Aug 13, 2009·Cancer Chemotherapy and Pharmacology·Yelena Y JanjigianNaiyer A Rizvi
Dec 31, 2003·Bioorganic & Medicinal Chemistry·Marie Hélène David-CordonnierChristian Bailly
Nov 1, 2003·Bioorganic & Medicinal Chemistry Letters·Ahmed KamalG Ramesh
Dec 31, 2003·Bioorganic & Medicinal Chemistry Letters·Ahmed KamalP Ramulu
Mar 12, 2004·Bioorganic & Medicinal Chemistry Letters·Luke A MastersonDavid E Thurston
Apr 28, 2004·Bioorganic & Medicinal Chemistry Letters·Ahmed KamalD Rajasekhar Reddy
Jun 2, 2005·Bioorganic & Medicinal Chemistry Letters·Georgios RotasDavid Mikeladze
Oct 13, 2001·Bioorganic & Medicinal Chemistry Letters·S J GregsonD E Thurston
Jul 13, 2002·Bioorganic & Medicinal Chemistry Letters·Ahmed KamalG Ramesh
Sep 25, 2003·Bioorganic & Medicinal Chemistry Letters·Ahmed KamalG Ramesh
Jun 16, 2001·Drug Discovery Today·A Westwell
Dec 21, 2010·Chemical Reviews·Dyeison Antonow, David E Thurston
Apr 2, 2005·Nature Reviews. Cancer·Stephen Neidle, David E Thurston
Jun 26, 2003·European Journal of Biochemistry·Marie-Hélène David-CordonnierChristian Bailly
Dec 18, 2007·Nucleic Acids Research·Johannes GrillariRegina Voglauer
Mar 24, 2011·Nucleic Acids Research·Khondaker M RahmanDavid E Thurston
Sep 8, 2011·Genes & Development·Anderson T WangPeter J McHugh
Feb 25, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Igor PuzanovMace L Rothenberg
Mar 22, 2002·The Lancet Oncology·P J McHughJ A Hartley
Oct 21, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Karl HemmingPaul A O'Gorman
Apr 5, 2011·Expert Opinion on Investigational Drugs·John A Hartley
Nov 12, 2015·International Journal of Molecular Sciences·Gaëlle Savreux-LengletMarie-Hélène David-Cordonnier
Apr 16, 2003·The Kaohsiung Journal of Medical Sciences·Wan-Ping HuJeh-Jeng Wang
Mar 14, 2007·International Journal of Antimicrobial Agents·Tsveta HadjivassilevaPeter W Taylor
Jun 15, 2010·Medicinal Research Reviews·Barbara Gerratana
Jul 28, 2005·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·S M GuichardD I Jodrell
Aug 19, 2015·BMC Veterinary Research·Maria Mellinas-GomezJohn A Hartley
Feb 1, 2006·Expert Opinion on Therapeutic Patents·Jinxia DengNouri Neamati
Nov 22, 2011·Cell Cycle·Blanka SengerováPeter J McHugh
Sep 30, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yong MaDonglu Zhang
Aug 19, 2014·PloS One·Khondaker M RahmanDavid E Thurston
Dec 15, 2006·European Journal of Medicinal Chemistry·Nageswara KodeShashikant Phadtare

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.