Novel Compounds for Treatment of Cancer and Disorders Associated with Angiogenesis Function

Abstract

Novel compounds for treatment of cancer and disorders associated with angiogenesis function. Also disclosed are a method of preparing the compounds, pharmaceutical compositions and packaged products containing the compounds, a method of using these molecules to treat cancer (e.g., leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, breast cancer, renal cancer, and prostate cancer) and disorders associated with angiogenesis function (e.g., age-related macular degeneration, macular dystrophy, and diabetes), a method of monitoring the treatment, a method of profiling gene expression, and a method of modulating cell growth, cell cycle, apoptosis, or gene expression.

1 . A compound of any of Formulas 1-19, 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein each of R1, R2, and R3 is a hydrogen, halogen, hydroxyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or an organic group containing 1-20 carbon atoms in a linear, branched, or cyclic structural format. 
     
   
   
       2 . The compound of  claim 1 , wherein the substituted alkyl, substituted alkenyl, substituted phenyl, substituted aryl, or substituted heteroaryl contains a halo, hydroxyl, alkoxy, alkylthio, phenoxy, aroxy, cyano, isocyano, carbonyl, carboxyl, amino, amido, sulfonyl, or substituted heterocyclic, sugar, or peptide substitution, and wherein the organic group includes a heteroatom of oxygen, sulfur, or nitrogen. 
   
   
       3 . A compound selected from the group consisting of SC20-37, SC201-266, SC268, and SC270-280. 
   
   
       4 . A method of modulating cell growth, cell cycle, or apoptosis, comprising contacting a cell with a compound of  claim 1  or  3 , thereby inhibiting cell growth, arresting cell cycle, or inducing apoptosis. 
   
   
       5 . The method of  claim 4 , wherein the cell is a leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, breast cancer, renal cancer, or prostate cancer cell. 
   
   
       6 . A method of modulating gene expressing in a cell, comprising contacting a cell with a compound of  claim 1  or  3 , thereby increasing or decreasing the expression of one or more genes in the cell. 
   
   
       7 . The method of  claim 6 , wherein the one or more genes are selected from the group consisting of BCL2, BCL2L1, JUN, JUNB, MAD, MAX, TNFRSF1A, TP53, NFKB1, TNFSF10, CASP1, PCNA, TNFAIP1, DAP, KDR, MAP3K14, CCNA2, CDC2, CDK7, CDK8, CDKN1A, CDKN1B, CDKN2A, CDKN2C, E2F1, E2F4, E2F5, MYC, RB1, RBL2, CCND3, CCNG1, CCNE1, CDC25C, TGFBR2, TGIF, TRAF4, CYP1A2, PTGS2, p21, p27, cyclin A, cdk1, p53, cyclin E, cdc25, p130, NFKB, c-MYC, COX2, Bcl-X L , annexin V, caspase 1, TNF receptor, microtubule-associated protein 4, microtubule affinity-regulating kinase 2, microtubule affinity-regulating kinase 4, transducer of ERBB2, vascular endothelial growth factor B, vascular endothelial growth factor, ankyrin repeat and MYND domain containing 1, RAB4B, putative prostate cancer tumor suppressor, pre-B-cell leukemia transcription factor 2, T-cell leukemia translocation altered gene, leukemia inhibitory factor, interferon regulatory factor 2 binding protein, interferon stimulated gene (20 kDa), interferon gamma receptor 2, 28 kD interferon responsive protein, polymerase (RNA) III, peroxisomal proliferator-activated receptor A interacting complex 285, RAD50 homolog ( S. cerevisiae ), MAX dimerization protein 3, kruppel-like factor 16, apolipoprotein L (6), X-ray repair complementing defective repair, mitogen-activated protein kinase 3, phosphatidylinositol 4-kinase type II, mitogen-activated protein kinase 12, protein kinase (AMP-activated, alpha 2 catalytic subunit), pyruvate dehydrogenase phosphatase regulatory subunit, phospholipase D3, inositol 1,4,5-triphosphate receptor (type 3), retinoic acid receptor (alpha), tumor necrosis factor receptor superfamily, Enolase 2 (gamma, neuronal), stanniocalcin 2, apelin, plexin B2, cathepsin Z, histone 1 (H2bc), histone 1 (H3h), β-tubulin, myc promoter-binding protein (MPB-1), retinoblastoma-binding protein 7, vimentin, enolase, phosphopyruvate hydratase beta, mitochondrial ATP synthase beta chain. 
   
   
       8 . A method of treating a subject, comprising administering to a subject in need thereof an effective amount of the compound of  claim 1  or  3 . 
   
   
       9 . The method of  claim 8 , wherein the subject is suffering from or at risk for developing cancer. 
   
   
       10 . The method of  claim 9 , wherein the cancer is leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, breast cancer, renal cancer, or prostate cancer. 
   
   
       11 . A pharmaceutical composition comprising an effective amount of one or more compounds of  claim 1  or  3  and a pharmaceutically acceptable carrier.