- Design, synthesis, and biological evaluation of novel sulindac derivatives as partial agonists of PPARγ with potential anti-diabetic efficacy
-
Peroxisome proliferator-activated receptor gamma (PPARγ) is a valuable drug target for diabetic treatment and ligands of PPARγ have shown potent anti-diabetic efficacy. However, to overcome the severe side effects of current PPARγ-targeted drugs, novel PPARγ ligands need to be developed. Sulindac, an identified ligand of PPARγ, is widely used in clinic as a non-steroidal anti-inflammatory drug. To explore its potential application for diabetes, we designed and synthesized a series of sulindac derivatives to investigate their structure-activity relationship as PPARγ ligand and potential anti-diabetic effect. We found that meta-substitution in sulindac's benzylidene moiety was beneficial to PPARγ binding and transactivation. Z rather than E configuration of the benzylidene double bond endowed derivatives with the selectivity of PPARγ activation. The indene fluorine is essential for binding and regulating PPARγ. Compared with rosiglitazone, compound 6b with benzyloxyl meta-substitution and Z benzylidene double bond weakly induced adipogenesis and PPARγ-targeted gene expression. However, 6b potently improved glucose tolerance in a diabetic mice model. Unlike rosiglitazone, 6b was devoid of apparent toxicity to osteoblastic formation. Thus, we provided some useful guidelines for PPARγ-based optimization of sulindac and an anti-diabetic lead compound with less side effects.
- Huang, Fengyu,Zeng, Zhiping,Zhang, Weidong,Yan, Zhiqiang,Chen, Jiayun,Yu, Liangfa,Yang, Qian,Li, Yihuan,Yu, Hongyu,Chen, Junjie,Wu, Caisheng,Zhang, Xiao-kun,Su, Ying,Zhou, Hu
-
-
- O-carborane derivative, synthesis method and application thereof
-
The invention discloses an o-carborane derivative and a synthesis method thereof. The method includes: step 1, taking 5-fluoro-2-methyl-1H-indene or 5-trifluoromethyl-2-methyl-1H-indene as a reactioninitiator, adopting aluminum trichloride as a catalyst, and carrying out reaction with 1-chloroacetic acid to obtain an intermediate 2; step 2, reacting the intermediate 2 with N-bromosuccinimide by taking DMF as a reaction solvent to obtain an intermediate 3; and step 3, reacting the intermediate 3 with o-carborane in an organic solvent or ionic liquid under an alkaline condition to obtain the corresponding o-carborane derivative. According to the invention, fluorine ions and relative hydrophilic groups are introduced for modification through chemical synthesis, the purposes of reducing toxicity and increasing compound polarity and cell affinity are achieved, so that the technical effect of targeted enrichment and high concentration of boron ions in tumor cells is achieved, and then the technical bottleneck that p-borane phenylalanine (BPA) is discharged by an anti-transport mechanism after the concentration of the BPA in the tumor cells reaches a certain number 1 is solved.
- -
-
Paragraph 0012; 0021-0022
(2020/06/17)
-
- Design, synthesis and biological evaluation of tetrazole-containing RXRα ligands as anticancer agents
-
Nuclear receptor RXRα plays an important role in many biological and pathological processes. The nongenomic action of RXRα is implicated in many cancers. K-8008, a non-canonical RXRα ligand derived from sulindac, inhibits the TNFα-activated PI3K/AKT pathway by mediating the interaction between a truncated form of RXRα (tRXRα) and the p85α regulatory subunit of PI3K and exerts potent anticancer activity in animal model. Herein we report our studies of a novel series of K-8008 analogs as potential anticancer agents targeting RXRα. Two compounds 8b and 18a were identified to have slightly stronger binding to RXRα and improved apoptotic activities in breast cancer cells.
- Yan, Zhiqiang,Chong, Shuyi,Lin, Huiyun,Yang, Qian,Wang, Xin,Zhang, Weidong,Zhang, Xiaokun,Zeng, Zhiping,Su, Ying
-
p. 562 - 575
(2019/01/10)
-
- COMPOUNDS, COMPOSITIONS AND METHODS OF TREATING CANCER
-
Disclosed are compounds of formulas I and II, in which R, R0, R1-R4, R7-R10, n, X, Y, Y', and E are as described herein, pharmaceutical compositions containing such compounds. The compounds and pharmaceutical compositions are for use in treating or preventing diseases, for example, cancer.
- -
-
-
- INDENYL COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, AND MEDICAL USES THEREOF
-
Disclosed are compounds, for example, compounds of formula I, wherein R, R0, R1-R8, n, X, Y, Y′, and E are as described herein, pharmaceutical compositions containing such compounds, and methods of treating or preventing a disease or condition, for example, cancer.
- -
-
-
- METHOD OF TREATING OR PREVENTING RAS-MEDIATED DISEASES
-
Disclosed are compounds, for example, a compound of formula I, wherein R, R0, R1-R8, n, X, Y, Y′, and E are as described herein, pharmaceutical compositions containing such compounds, and methods of treating or preventing a disease or condition for example, cancer, mediated by the ras gene.
- -
-
-
- Method for treating a patient with neoplasia using Iressa
-
This invention provides a method for treating a patient with neoplasia by an adjuvant therapy that includes treatment with an inhibitor of human epidermal growth factor receptor tyrosine kinase and a cGMP-specific phosphodiesterase inhibitor.
- -
-
-
- Methods for treatment of rheumatoid arthritis
-
Substituted condensation products of N-benzyl-3-indenylacetamides with heterocyclic aldehydes and other such inhibitors are useful for the treatment of rheumatoid arthritis.
- -
-
-
- Methods for treatment of diseases where GSK 3-beta is desired, and methods to identify compounds usefule for that
-
A method for selecting compounds for the treatment of diseases where GSK3β is desired includes assessing whether the compounds cause an increase in PKG activity in the tissue of interest.
- -
-
-
- Methods for treatment of multiple sclerosis
-
Substituted condensation products of N-benzyl-3-indenylacetamides with heterocyclic aldehydes and other such inhibitors are useful for the treatment of multiple sclerosis.
- -
-
-
- Methods for treatment of lupus erythematosus
-
Substituted condensation products of N-benzyl-3-indenylacetamides with heterocyclic aldehydes and other such inhibitors are useful for the treatment of lupus erythematosus.
- -
-
-
- Methods for treatment of renal cell carcinoma
-
A method of treating renal cell carcinoma in a mammal with that disease comprising administering to the mammal a physiologically effective amount of an inhibitor of PDE10.
- -
-
-
- Methods for treatment of scleroderma
-
Substituted condensation products of N-benzyl-3-indenylacetamides with heterocyclic aldehydes and other such inhibitors are useful for the treatment of scleroderma.
- -
-
-
- Methods for treatment of cystic fibrosis
-
Substituted condensation products of N-benzyl-3-indenylacetamides with heterocyclic aldehydes and other such inhibitors are useful for the treatment of cystic fibrosis.
- -
-
-
- Methods for treatment of type I diabetes
-
Substituted condensation products of -benzyl-3-indenylacetamides with heterocyclic aldehydes and other such inhibitors are useful for the treatment of type I diabetes.
- -
-
-
- Method for treating patient having precancerous lesions with a combination of pyrimidopyrimidine derivatives and esters and amides of substituted indenyl acetic acides
-
Combinations of substituted indenyl acetic acids and pyrimido-pyrimidine derivatives are useful in the treatment of colonic polyps and inhibiting the growth of neoplastic cells.
- -
-
-
- Substituted condensation products of 1H-indenyl-hydroxyalkanes with aldehydes for neoplasia
-
Substituted condensation products of 1H-indenylhydroxyalkanes with aldehydes are useful for inducing or promoting apoptosis and for arresting uncontrolled neoplastic cell proliferation, and are specifically useful in the arresting and treatment of neoplasia, including precancerous and cancerous lesions.
- -
-
-
- Substituted condensation products of N-benzyl-3-indenylacetamides heterocyclic aldehydes for neoplasia
-
Substituted condensation products of N-benzyl-3-indenylacetamides with heterocyclic aldehydes are useful for inducing or promoting apotosis and for arresting uncontrolled neoplastic cell proliferation, and are specifically useful in the arresting and treatment of neoplasias, including precancerous and cancerous lesions.
- -
-
-
- Method for treating patients having precancerous lesions with substituted indene derivatives
-
Substituted indene derivatives are useful for treating patients having precancerous lesions and for inhibiting the growth of neoplastic cells.
- -
-
-
- Substituted condensation products of n-benzyl-3-indenyl acetamides with heterocyclic aldehydes
-
Substituted condensation products of N-benzyl-3-indenylacetamides with heterocyclic aldehydes are useful for inducing or promoting apotosis and for arresting uncontrolled neoplastic cell proliferation, and are specifically useful in the arresting and treatment of neoplasias, including precancerous and cancerous lesions.
- -
-
-
- Substituted methoxy benzylidene indenyl-acetic and propionic acids for treating patients with precancerous lesions
-
Substituted methoxy benzylidene indenyl compounds are useful in the treatment of precancerous lesions and neoplasms.
- -
-
-
- Lactone compounds for treating patient with precancerous lesions
-
Substituted lactone compounds are useful in the treatment of precancerous lesions and neoplasms.
- -
-
-
- Lactone compounds for treating patients with precancerous lesions
-
Substituted lactone compounds are useful in the treatment of precancerous lesions.
- -
-
-
- Method for treating patients with precancerous lesions by administering substituted sulfonyl idenyl acetic and propionic acids and esters to patients with lesions sensitive to such compounds
-
Substituted indenyl sulfonyl acetic acids are useful in the treatment of precancerous lesions sensitive to treatment with those sulfonyl compounds.
- -
-
-
- Esters and amides of substituted indenyl acetic acids
-
Esters and amides of substituted indenyl acetic acids of the formula: n is an integer of at least 2;, Q is a deprotonated residue of polymer or macromolecular structure having a molecular weight of at least about 1000 containing at least two primary and/or secondary amino groups and/or hydroxy groups;, R1 is selected from hydrogen, lower alkyl, or haloalkyl;, R2 is selected from hydrogen or alkyl;, R3 and R4 are one or more members each independently chosen from hydrogen, alkyl, acyloxy, alkoxy, nitro, amino, acylamino, alkylamino, diakylamino, dialkylaminoalkyl, sulfamyl, alkythio, mercapto, hydroxy, hydroxyalkyl, alkylsulfonyl, halogen, cyano, carboxyl, carbalkoxy, carbamido, haloalkyl or cycloalkoxy; and, R5 is selected from alkylsulfenyl, alkylsulfinyl or alkylsulfonyl. are useful in the treatment of colonic polyps.
- -
-
-