SULINDAC SULFIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C20H17FO2S
Molecular Weight	340.411
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CSC1=CC=C(\C=C2\C(C)=C(CC(O)=O)C3=C2C=CC(F)=C3)C=C1

InChI

InChIKey=LFWHFZJPXXOYNR-MFOYZWKCSA-N

InChI=1S/C20H17FO2S/c1-12-17(9-13-3-6-15(24-2)7-4-13)16-8-5-14(21)10-19(16)18(12)11-20(22)23/h3-10H,11H2,1-2H3,(H,22,23)/b17-9-

HIDE SMILES / InChI

Molecular Formula	C20H17FO2S
Molecular Weight	340.411
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	1
Optical Activity	NONE

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/9778042 | https://www.ncbi.nlm.nih.gov/pubmed/28276667 | https://www.ncbi.nlm.nih.gov/pubmed/10933052

Sulindac sulfide, an active metabolite of the nonsteroidal anti-inflammatory drug (NSAID) sulindac, directly binds to the Ras gene product p21ras in a non-covalent manner. Sulindac sulfide strongly inhibits Ras-induced malignant transformation and Ras/Raf dependent transactivation, due to its action at the most critical site in Ras signaling. Sulindac sulfide was proposed as a lead compound in the search for novel anti-cancer drugs, which directly inhibit Ras-mediated cell proliferation and malignant transformation. Experiments on rodents have revealed that sulindac sulfide effectively inhibited tumor growth in colorectal cancer cell xenografts mice. In addition, was shown, that sulindac sulfide inhibited ABCC1-mediated transport of appropriate endogenous and xenobiotic substrates. The drug was selectivity for ABCC1 as compared with ABCB1 and ABCG2. These properties allow designing novel ABCC1 inhibitors by chemically modifying sulindac sulfide to improve potency and selectivity to inhibit ABCC1-mediated efflux for preventing drug resistance and tumor recurrence or secondary tumor formation following chemotherapy.

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
GTPase HRas 2 Target ID: P01112 Gene ID: 3265.0 Gene Symbol: HRAS Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/9778042	Inhibitor 8297
Multidrug resistance-associated protein 1 15 Target ID: P33527\|\|\|Q9UQ99 Gene ID: 4363.0 Gene Symbol: ABCC1 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/28276667	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Colorectal cancer 101 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10933052	Primary		Preclinical	Unknown Approved Use Unknown

PubMed

Title	Date	PubMed
Apoptosis primarily accounts for the growth-inhibitory properties of sulindac metabolites and involves a mechanism that is independent of cyclooxygenase inhibition, cell cycle arrest, and p53 induction.	1997 Jun 15	9192825
PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs.	1999 Oct 29	10555149
Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines: growth inhibition by nonsteroidal anti-inflammatory drugs.	1999 Sep 1	10485483
The effect of NSAIDs and a COX-2 specific inhibitor on Helicobacter pylori-induced PGE2 and HGF in human gastric fibroblasts.	2000 Apr	10807402
Colon cancer chemopreventive drugs modulate integrin-mediated signaling pathways.	2000 Mar	10741720
Sulindac sulfide-induced apoptosis involves death receptor 5 and the caspase 8-dependent pathway in human colon and prostate cancer cells.	2001 Sep 15	11559570
Constitutive activation of NF-kappaB in Ki-ras-transformed prostate epithelial cells.	2002 Jul 4	12085227
Requirement of BAX for TRAIL/Apo2L-induced apoptosis of colorectal cancers: synergism with sulindac-mediated inhibition of Bcl-x(L).	2002 Mar 15	11912124
Peroxisome proliferator-activated receptor-gamma is a target of nonsteroidal anti-inflammatory drugs mediating cyclooxygenase-independent inhibition of lung cancer cell growth.	2002 Nov	12391285
Cyclooxygenase-2 overexpression inhibits death receptor 5 expression and confers resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human colon cancer cells.	2002 Sep 1	12208739
Apo2L/TRAIL differentially modulates the apoptotic effects of sulindac and a COX-2 selective non-steroidal anti-inflammatory agent in Bax-deficient cells.	2002 Sep 5	12203115
Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid beta 42 production by direct modulation of gamma-secretase activity.	2003 Aug 22	12805356
Glutathione-S-transferase P1-1 protects aberrant crypt foci from apoptosis induced by deoxycholic acid.	2004 Aug	15300575
Purification and characterization of the human gamma-secretase complex.	2004 Aug 3	15274632
Cyclooxygenase inhibitors induce apoptosis in oral cavity cancer cells by increased expression of nonsteroidal anti-inflammatory drug-activated gene.	2004 Dec 24	15555568
Sulindac targets nuclear beta-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines.	2004 Jan 12	14710233
Effect of nonsteroidal anti-inflammatory drugs on beta-catenin protein levels and catenin-related transcription in human colorectal cancer cells.	2004 Jul 5	15188006
Both PPARgamma and PPARdelta influence sulindac sulfide-mediated p21WAF1/CIP1 upregulation in a human prostate epithelial cell line.	2005 Dec 8	16091736
The cyclooxygenase inhibitor indomethacin modulates gene expression and represses the extracellular matrix protein laminin gamma1 in human glioblastoma cells.	2005 Jan 15	15561105
The conventional nonsteroidal anti-inflammatory drug sulindac sulfide arrests ovarian cancer cell growth via the expression of NAG-1/MIC-1/GDF-15.	2005 Mar	15767558
Structural determinants of arylacetic acid nonsteroidal anti-inflammatory drugs necessary for binding and activation of the prostaglandin D2 receptor CRTH2.	2005 Mar	15563582
Transcriptional regulation of activating transcription factor 3 involves the early growth response-1 gene.	2005 Nov	16079301
Id-1 gene downregulation by sulindac sulfide and its upregulation during tumor development in gastric cancer.	2006 Mar 15	16184548
Arachidonic acid-induced gene expression in colon cancer cells.	2006 Oct	16704987
Nonsteroidal anti-inflammatory drugs induce colorectal cancer cell apoptosis by suppressing 14-3-3epsilon.	2007 Apr 1	17409426
Signal peptide peptidase and gamma-secretase share equivalent inhibitor binding pharmacology.	2007 Dec 21	17932033
Genetic polymorphisms of human flavin-containing monooxygenase 3: implications for drug metabolism and clinical perspectives.	2007 Jun	17559352
Malignant transformation of normal enterocytes following downregulation of Bak expression.	2008	18349538
Cyclooxygenase inhibitors induce apoptosis in sinonasal cancer cells by increased expression of nonsteroidal anti-inflammatory drug-activated gene.	2008 Apr 15	18076062
Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation.	2008 Aug 29	18759972
Phosphatidylinositol acts through mitogen-activated protein kinase to stimulate hepatic apolipoprotein A-I secretion.	2008 Dec	19013290
Generation of Abeta38 and Abeta42 is independently and differentially affected by familial Alzheimer disease-associated presenilin mutations and gamma-secretase modulation.	2008 Jan 11	17962197
Independent generation of Abeta42 and Abeta38 peptide species by gamma-secretase.	2008 Jun 20	18426795
Effects of sulindac sulfide on the membrane architecture and the activity of gamma-secretase.	2008 May	18359496
Nonsteroidal anti-inflammatory drugs induced endothelial apoptosis by perturbing peroxisome proliferator-activated receptor-delta transcriptional pathway.	2008 Nov	18678619
Sulindac metabolites induce proteosomal and lysosomal degradation of the epidermal growth factor receptor.	2010 Apr	20332299
The dietary compounds resveratrol and genistein induce activating transcription factor 3 while suppressing inhibitor of DNA binding/differentiation-1.	2011 Jun	21554132
Silibinin induces apoptosis of HT29 colon carcinoma cells through early growth response-1 (EGR-1)-mediated non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) up-regulation.	2014 Mar 25	24440808

Patents

Sample Use Guides

In Vivo Use Guide

Colorectal Cancer Cell Xenografts mice: sulindac sulfide was used at a dose of 10 mg/kg every other day to treat HCA-7 xenografts that had been implanted 7 weeks earlier. In this experiment, a significant reduction in tumor growth was observed within 2 weeks of treatment initiation.

Route of Administration: Intraperitoneal

In Vitro Use Guide

Sulindac sulfide and inhibited colorectal cancer cell line, HCA-7 HCA-7 and HCT-116 cell growth in vitro. Both HCA-7 and HCT-116 cells showed equivalent reductions in colony number with sulfide treatment (< 50 µmol/L).

Substance Class	Chemical Created by `admin` on `Fri Dec 15 18:38:26 GMT 2023` Edited by `admin` on `Fri Dec 15 18:38:26 GMT 2023`
Record UNII	6UVA8S2DEY
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

SULINDAC SULFIDE

Common Name

English

Z-SULINDAC SULFIDE

Common Name

English

SULINDAC SULFIDE, (Z)-

Common Name

English

1H-INDENE-3-ACETIC ACID, 5-FLUORO-2-METHYL-1-((4-(METHYLTHIO)PHENYL)METHYLENE)-, (1Z)-

Common Name

English

SULINDAC RELATED COMPOUND C [USP IMPURITY]

Common Name

English

CIS-SULINDAC SULFIDE

Common Name

English

SULINDAC RELATED COMPOUND C

Common Name

English

SULINDAC IMPURITY C [EP IMPURITY]

Common Name

English

SULINDAC SULPHIDE, (Z)-

Common Name

English

SULINDAC RELATED COMPOUND C [USP-RS]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C1323