Structure-activity relationships of monomeric C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antitumor agents

D Antonow; M Kaliszczak; GD Kang; M Coffils; AC Tiberghien; N Cooper; T Barata; S Heidelberger; CH James; M Zloh; TC Jenkins; AP Reszka; S Neidle; SM Guichard; DI Jodrell; JA Hartley; PW Howard; DE Thurston

doi:10.1021/jm901722v

Structure-activity relationships of monomeric C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antitumor agents

D Antonow, M Kaliszczak, GD Kang, M Coffils, AC Tiberghien, N Cooper, T Barata, S Heidelberger, CH James, M Zloh, TC Jenkins, AP Reszka, S Neidle, SM Guichard, DI Jodrell, JA Hartley, PW Howard, DE Thurston

Institute of Pharmaceutical Science

Research output: Contribution to journal › Article › peer-review

42 Citations (Scopus)

Abstract

A comprehensive SAR investigation of the C2-position of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) monomer antitumor agents is reported, establishing the molecular requirements for optimal in vitro cytotoxicity and DNA-binding affinity. Both carbocyclic and heterocyclic C2-aryl substituents have been studied ranging from single aryl rings to fused ring systems, and also styryl substituents, establishing across a library of 80 analogues that C2-aryl and styryl substituents significantly enhance both DNA-binding affinity and in vitro cytotoxicity, with a correlation between the two. The optimal C2-grouping for both DNA-binding affinity and cytotoxicity was found to be the C2-quinolinyl moiety which, according to molecular modeling, is due to the overall fit of the molecule in the DNA minor groove, and potential specific contacts with functional groups in the floor and walls of the groove. This analogue (14l) was shown to delay tumor growth in a HCT-116 (bowel) human tumor xenograft model.

Original language	English
Article number	N/A
Pages (from-to)	2927 - 2941
Number of pages	15
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	7
DOIs	https://doi.org/10.1021/jm901722v
Publication status	Published - 8 Apr 2010

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1021/jm901722v

Cite this

Antonow, D., Kaliszczak, M., Kang, GD., Coffils, M., Tiberghien, AC., Cooper, N., Barata, T., Heidelberger, S., James, CH., Zloh, M., Jenkins, TC., Reszka, AP., Neidle, S., Guichard, SM., Jodrell, DI., Hartley, JA., Howard, PW., & Thurston, DE. (2010). Structure-activity relationships of monomeric C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antitumor agents. Journal of Medicinal Chemistry, 53(7), 2927 - 2941 . Article N/A. https://doi.org/10.1021/jm901722v

@article{d15bd50642f541e79e1a48158a700cd3,

title = "Structure-activity relationships of monomeric C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antitumor agents",

abstract = "A comprehensive SAR investigation of the C2-position of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) monomer antitumor agents is reported, establishing the molecular requirements for optimal in vitro cytotoxicity and DNA-binding affinity. Both carbocyclic and heterocyclic C2-aryl substituents have been studied ranging from single aryl rings to fused ring systems, and also styryl substituents, establishing across a library of 80 analogues that C2-aryl and styryl substituents significantly enhance both DNA-binding affinity and in vitro cytotoxicity, with a correlation between the two. The optimal C2-grouping for both DNA-binding affinity and cytotoxicity was found to be the C2-quinolinyl moiety which, according to molecular modeling, is due to the overall fit of the molecule in the DNA minor groove, and potential specific contacts with functional groups in the floor and walls of the groove. This analogue (14l) was shown to delay tumor growth in a HCT-116 (bowel) human tumor xenograft model.",

author = "D Antonow and M Kaliszczak and GD Kang and M Coffils and AC Tiberghien and N Cooper and T Barata and S Heidelberger and CH James and M Zloh and TC Jenkins and AP Reszka and S Neidle and SM Guichard and DI Jodrell and JA Hartley and PW Howard and DE Thurston",

year = "2010",

month = apr,

day = "8",

doi = "10.1021/jm901722v",

language = "English",

volume = "53",

pages = "2927 -- 2941 ",

journal = "Journal of Medicinal Chemistry",

publisher = "American Chemical Society",

number = "7",

}

Antonow, D, Kaliszczak, M, Kang, GD, Coffils, M, Tiberghien, AC, Cooper, N, Barata, T, Heidelberger, S, James, CH, Zloh, M, Jenkins, TC, Reszka, AP, Neidle, S, Guichard, SM, Jodrell, DI, Hartley, JA, Howard, PW & Thurston, DE 2010, 'Structure-activity relationships of monomeric C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antitumor agents', Journal of Medicinal Chemistry, vol. 53, no. 7, N/A, pp. 2927 - 2941 . https://doi.org/10.1021/jm901722v

TY - JOUR

T1 - Structure-activity relationships of monomeric C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antitumor agents

AU - Antonow, D

AU - Kaliszczak, M

AU - Kang, GD

AU - Coffils, M

AU - Tiberghien, AC

AU - Cooper, N

AU - Barata, T

AU - Heidelberger, S

AU - James, CH

AU - Zloh, M

AU - Jenkins, TC

AU - Reszka, AP

AU - Neidle, S

AU - Guichard, SM

AU - Jodrell, DI

AU - Hartley, JA

AU - Howard, PW

AU - Thurston, DE

PY - 2010/4/8

Y1 - 2010/4/8

N2 - A comprehensive SAR investigation of the C2-position of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) monomer antitumor agents is reported, establishing the molecular requirements for optimal in vitro cytotoxicity and DNA-binding affinity. Both carbocyclic and heterocyclic C2-aryl substituents have been studied ranging from single aryl rings to fused ring systems, and also styryl substituents, establishing across a library of 80 analogues that C2-aryl and styryl substituents significantly enhance both DNA-binding affinity and in vitro cytotoxicity, with a correlation between the two. The optimal C2-grouping for both DNA-binding affinity and cytotoxicity was found to be the C2-quinolinyl moiety which, according to molecular modeling, is due to the overall fit of the molecule in the DNA minor groove, and potential specific contacts with functional groups in the floor and walls of the groove. This analogue (14l) was shown to delay tumor growth in a HCT-116 (bowel) human tumor xenograft model.

AB - A comprehensive SAR investigation of the C2-position of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) monomer antitumor agents is reported, establishing the molecular requirements for optimal in vitro cytotoxicity and DNA-binding affinity. Both carbocyclic and heterocyclic C2-aryl substituents have been studied ranging from single aryl rings to fused ring systems, and also styryl substituents, establishing across a library of 80 analogues that C2-aryl and styryl substituents significantly enhance both DNA-binding affinity and in vitro cytotoxicity, with a correlation between the two. The optimal C2-grouping for both DNA-binding affinity and cytotoxicity was found to be the C2-quinolinyl moiety which, according to molecular modeling, is due to the overall fit of the molecule in the DNA minor groove, and potential specific contacts with functional groups in the floor and walls of the groove. This analogue (14l) was shown to delay tumor growth in a HCT-116 (bowel) human tumor xenograft model.

U2 - 10.1021/jm901722v

DO - 10.1021/jm901722v

M3 - Article

VL - 53

SP - 2927

EP - 2941

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 7

M1 - N/A

ER -

Structure-activity relationships of monomeric C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antitumor agents

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this