Marinopyrrole derivatives with sulfide spacers as selective disruptors of Mcl-1 binding to pro-apoptotic protein bim

Chunwei Cheng; Yan Liu; Maria E. Balasis; Thomas P. Garner; Jerry Li; Nicholas L. Simmons; Norbert Berndt; Hao Song; Lili Pan; Yong Qin; K. C. Nicolaou; Evripidis Gavathiotis; Said M. Sebti; Rongshi Li

doi:10.3390/md12084311

Marinopyrrole derivatives with sulfide spacers as selective disruptors of Mcl-1 binding to pro-apoptotic protein bim

Chunwei Cheng, Yan Liu, Maria E. Balasis, Thomas P. Garner, Jerry Li, Nicholas L. Simmons, Norbert Berndt, Hao Song, Lili Pan, Yong Qin, K. C. Nicolaou, Evripidis Gavathiotis, Said M. Sebti, Rongshi Li

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

11 Scopus citations

Abstract

A series of novel marinopyrroles with sulfide and sulphone spacers were designed and synthesized. Their activity to disrupt the binding of the pro-apoptotic protein, Bim, to the pro-survival proteins, Mcl-1 and Bcl-xL, was evaluated using ELISA assays. Fluorescence-quenching (FQ) assays confirmed the direct binding of marinopyrroles to Mcl-1. Benzyl-and benzyl methoxy-containing sulfide derivatives 4 and 5 were highly potent dual Mcl-1/Bim and Bcl-xL/Bim disruptors (IC₅₀ values of 600 and 700 nM), whereas carboxylate-containing sulfide derivative 9 exhibited 16.4-fold more selectivity for disrupting Mcl-1/Bim over Bcl-xL/Bim binding. In addition, a nonsymmetrical marinopyrrole 12 is as equally potent as the parent marinopyrrole A (1) for disrupting both Mcl-1/Bim and Bcl-xL/Bim binding. Some of the derivatives were also active in intact human breast cancer cells where they reduced the levels of Mcl-1, induced programd cell death (apoptosis) and inhibited cell proliferation.

Original language	English (US)
Pages (from-to)	4311-4325
Number of pages	15
Journal	Marine Drugs
Volume	12
Issue number	8
DOIs	https://doi.org/10.3390/md12084311
State	Published - Aug 1 2014
Externally published	Yes

Keywords

Apoptosis
Marinopyrroles
Protein-protein interaction disruptors
SAR

ASJC Scopus subject areas

Pharmaceutical Science
Drug Discovery
Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

UN SDGs

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

Access to Document

10.3390/md12084311

Cite this

@article{26bd8051d04f41178f12a3c928fffcd3,

title = "Marinopyrrole derivatives with sulfide spacers as selective disruptors of Mcl-1 binding to pro-apoptotic protein bim",

abstract = "A series of novel marinopyrroles with sulfide and sulphone spacers were designed and synthesized. Their activity to disrupt the binding of the pro-apoptotic protein, Bim, to the pro-survival proteins, Mcl-1 and Bcl-xL, was evaluated using ELISA assays. Fluorescence-quenching (FQ) assays confirmed the direct binding of marinopyrroles to Mcl-1. Benzyl-and benzyl methoxy-containing sulfide derivatives 4 and 5 were highly potent dual Mcl-1/Bim and Bcl-xL/Bim disruptors (IC50 values of 600 and 700 nM), whereas carboxylate-containing sulfide derivative 9 exhibited 16.4-fold more selectivity for disrupting Mcl-1/Bim over Bcl-xL/Bim binding. In addition, a nonsymmetrical marinopyrrole 12 is as equally potent as the parent marinopyrrole A (1) for disrupting both Mcl-1/Bim and Bcl-xL/Bim binding. Some of the derivatives were also active in intact human breast cancer cells where they reduced the levels of Mcl-1, induced programd cell death (apoptosis) and inhibited cell proliferation.",

keywords = "Apoptosis, Marinopyrroles, Protein-protein interaction disruptors, SAR",

author = "Chunwei Cheng and Yan Liu and Balasis, {Maria E.} and Garner, {Thomas P.} and Jerry Li and Simmons, {Nicholas L.} and Norbert Berndt and Hao Song and Lili Pan and Yong Qin and Nicolaou, {K. C.} and Evripidis Gavathiotis and Sebti, {Said M.} and Rongshi Li",

note = "Publisher Copyright: {\textcopyright} 2014 by the authors; licensee MDPI, Basel, Switzerland.",

year = "2014",

month = aug,

day = "1",

doi = "10.3390/md12084311",

language = "English (US)",

volume = "12",

pages = "4311--4325",

journal = "Marine Drugs",

issn = "1660-3397",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "8",

}

TY - JOUR

T1 - Marinopyrrole derivatives with sulfide spacers as selective disruptors of Mcl-1 binding to pro-apoptotic protein bim

AU - Cheng, Chunwei

AU - Liu, Yan

AU - Balasis, Maria E.

AU - Garner, Thomas P.

AU - Li, Jerry

AU - Simmons, Nicholas L.

AU - Berndt, Norbert

AU - Song, Hao

AU - Pan, Lili

AU - Qin, Yong

AU - Nicolaou, K. C.

AU - Gavathiotis, Evripidis

AU - Sebti, Said M.

AU - Li, Rongshi

PY - 2014/8/1

Y1 - 2014/8/1

N2 - A series of novel marinopyrroles with sulfide and sulphone spacers were designed and synthesized. Their activity to disrupt the binding of the pro-apoptotic protein, Bim, to the pro-survival proteins, Mcl-1 and Bcl-xL, was evaluated using ELISA assays. Fluorescence-quenching (FQ) assays confirmed the direct binding of marinopyrroles to Mcl-1. Benzyl-and benzyl methoxy-containing sulfide derivatives 4 and 5 were highly potent dual Mcl-1/Bim and Bcl-xL/Bim disruptors (IC50 values of 600 and 700 nM), whereas carboxylate-containing sulfide derivative 9 exhibited 16.4-fold more selectivity for disrupting Mcl-1/Bim over Bcl-xL/Bim binding. In addition, a nonsymmetrical marinopyrrole 12 is as equally potent as the parent marinopyrrole A (1) for disrupting both Mcl-1/Bim and Bcl-xL/Bim binding. Some of the derivatives were also active in intact human breast cancer cells where they reduced the levels of Mcl-1, induced programd cell death (apoptosis) and inhibited cell proliferation.

AB - A series of novel marinopyrroles with sulfide and sulphone spacers were designed and synthesized. Their activity to disrupt the binding of the pro-apoptotic protein, Bim, to the pro-survival proteins, Mcl-1 and Bcl-xL, was evaluated using ELISA assays. Fluorescence-quenching (FQ) assays confirmed the direct binding of marinopyrroles to Mcl-1. Benzyl-and benzyl methoxy-containing sulfide derivatives 4 and 5 were highly potent dual Mcl-1/Bim and Bcl-xL/Bim disruptors (IC50 values of 600 and 700 nM), whereas carboxylate-containing sulfide derivative 9 exhibited 16.4-fold more selectivity for disrupting Mcl-1/Bim over Bcl-xL/Bim binding. In addition, a nonsymmetrical marinopyrrole 12 is as equally potent as the parent marinopyrrole A (1) for disrupting both Mcl-1/Bim and Bcl-xL/Bim binding. Some of the derivatives were also active in intact human breast cancer cells where they reduced the levels of Mcl-1, induced programd cell death (apoptosis) and inhibited cell proliferation.

KW - Apoptosis

KW - Marinopyrroles

KW - Protein-protein interaction disruptors

KW - SAR

UR - http://www.scopus.com/inward/record.url?scp=84908072746&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908072746&partnerID=8YFLogxK

U2 - 10.3390/md12084311

DO - 10.3390/md12084311

M3 - Article

C2 - 25076060

AN - SCOPUS:84908072746

SN - 1660-3397

VL - 12

SP - 4311

EP - 4325

JO - Marine Drugs

JF - Marine Drugs

IS - 8

ER -

Marinopyrrole derivatives with sulfide spacers as selective disruptors of Mcl-1 binding to pro-apoptotic protein bim

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this