pmx-464 and Colonic-Neoplasms

Interaction of 2-iodoaniline or 5-fluoro-2-iodoaniline with a range of arylsulfonyl chlorides affords sulfonamides that undergo Sonogashira couplings under thermal or microwave conditions with the alkyne 4-ethynyl-4-hydroxycyclohexa-2,5-dien-1-one followed by cyclization to 4-[1-(arylsulfonyl-1H-indol-2-yl)]-4-hydroxycyclo-hexa-2,5-dien-1-ones. This method allows for incorporation of a range of substituents into the arylsulfonyl moiety, and compounds showed selective in vitro inhibition of cancer cell lines of colon and renal origin, a feature of compounds bearing the quinol pharmacophore.

Topics: Antineoplastic Agents; Cell Line, Tumor; Colonic Neoplasms; Cyclohexenes; Drug Screening Assays, Antitumor; Humans; Indoles; Kidney Neoplasms; Structure-Activity Relationship; Sulfones

AW464 (NSC 706704) is a novel benzothiazole substituted quinol compound active against colon, renal and certain breast cancer cell lines. NCI COMPARE analysis indicates possible interaction with thioredoxin/thioredoxin reductase, which is upregulated under hypoxia. Through activity on HIF1alpha, VEGF levels are regulated and angiogenesis controlled. A thioredoxin inhibitor could therefore exhibit enhanced hypoxic toxicity and indirect antiangiogenic effects. In vitro experiments were performed on colorectal and breast cancer cell lines under both normoxic and hypoxic conditions and results compared against those obtained with normal cell lines, fibroblasts and keratinocytes. Antiangiogenic effects were studied using both large and microvessel cells. Indirect antiangiogenic effects (production of angiogenic growth factors) were studied via ELISA. We show that AW464 exerts antiproliferative effects on tumour cell lines as well as endothelial cells with an IC(50) of approximately 0.5 microM. Fibroblasts are however resistant. Proliferating, rather than quiescent, endothelial cells are sensitive to the drug indicating potential antiangiogenic rather than antivascular action. Endothelial differentiation is also inhibited in vitro. Hypoxia (1% O(2) for 48 h) sensitises colorectal cells to lower drug concentrations, and in HT29s greater inhibition of VEGF is observed under such conditions. In contrast, bFGF levels are unaffected, suggesting possible involvement of HIF1alpha. Thus, AW464 is a promising chemotherapeutic drug that may have enhanced potency under hypoxic conditions and also additional antiangiogenic activity.

Topics: Antineoplastic Agents; Benzothiazoles; Breast Neoplasms; Cell Line, Tumor; Colonic Neoplasms; Cyclohexanones; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Fibroblast Growth Factor 2; Fibroblasts; Humans; Hypoxia; In Vitro Techniques; Neovascularization, Pathologic; Thiazoles

Heteroaromatic quinols 4-(benzothiazol-2-yl)-4-hydroxycyclohexa-2,5-dienone (1) and 4-(1-benzenesulfonyl-1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dienone (2) exhibit potent and selective antitumor activity against colon, renal, and breast carcinoma cell lines in vitro (GI50 < 500 nmol/L). In vivo growth inhibition of renal, colon, and breast xenografts has been observed. Profound G2-M cell cycle block accompanied down-regulation of cdk1 gene transcription was corroborated by decreased CDK1 protein expression following treatment of HCT 116 cells with growth inhibitory concentrations of 1 or 2. The chemical structure of the quinol pharmacophore 4-(hydroxycyclohexa-2,5-dienone) suggested that these novel agents would readily react with nucleophiles in a double Michael (beta-carbon) addition. Indeed, COMPARE analysis within the National Cancer Institute database revealed a number of chemically related quinone derivatives that could potentially react with sulfur nucleophiles in a similar manner and suggested that thioredoxin/thioredoxin reductase signal transduction could be a putative target. Molecular modeling predicted covalent irreversible binding between quinol analogues and cysteine residues 32 and 35 of thioredoxin, thereby inhibiting enzyme activity. Binding has been confirmed, via mass spectrometry, between reduced human thioredoxin and 1. Microarray analyses of untreated HCT 116 cells and those exposed to either 1 (1 micromol/L) or 2 (500 nmol/L and 1 micromol/L) determined that of > or =10,000 cancer-related genes, expression of thioredoxin reductase was up-regulated >3-fold. Furthermore, quinols 1 and 2 inhibited insulin reduction, catalyzed by thioredoxin/thioredoxin reductase signaling in a dose-dependent manner (IC50 < 6 micromol/L). Results are consistent with a mechanism of action of novel antitumor quinols involving inhibition of the small redox protein thioredoxin.

Topics: Amino Acid Sequence; Antineoplastic Agents; Benzothiazoles; Blotting, Western; Breast Neoplasms; Cell Cycle; Cell Growth Processes; Cell Line, Tumor; Colonic Neoplasms; Cyclohexanones; Drug Screening Assays, Antitumor; Humans; Hydroquinones; Insulin; Mass Spectrometry; Molecular Sequence Data; Oligonucleotide Array Sequence Analysis; Sulfones; Thiazoles; Thioredoxins

The synthesis and antitumor evaluation of a series of new heteroaromatic- and aromatic-substituted hydroxycyclohexadienones ("quinols"), and their imine counterparts, are described. The quinols were synthesized via the addition of a lithiated aromatic moiety to a quinone ketal followed by deprotection. When the aromatic portion of the molecule is a fused heterobicyclic structure (e.g., benzothiazole derivative 7a), potent in vitro antitumor activity was observed in HCT 116 (GI50 = 40 nM) and HT 29 (GI50 = 380 nM) human colon as well in as MCF-7 and MDA 468 human breast cancer cell lines. When examined on the NCI Developmental Therapeutics Screening Program in vitro screen (60 human cancer cell lines), active compounds in this series consistently displayed a highly unusual pattern of selectivity; cytotoxicity (LC50) was concentrated in certain colon and renal cell lines only. Analogue 7a also showed in vivo antitumor activity against human RXF 944XL renal xenografts in nude NMRI mice and is the focus of further study.

Topics: Algorithms; Animals; Antineoplastic Agents; Benzothiazoles; Colonic Neoplasms; Computer Simulation; Cyclohexanes; Cyclohexanones; Drug Screening Assays, Antitumor; Humans; Kidney Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Structure-Activity Relationship; Thiazoles; Transplantation, Heterologous; Tumor Cells, Cultured