•Novel napthalamide-isoselnocyanate and -selenourea analogs were synthesized.•The isoselnocyanate analog NISC-6 was identified as the most effective compound.•NISC-6 inhibited growth of melanoma cell lines with both WT or mutant BRAF.•NISC-6 was dual inhibitor of in vitro Topo-IIα activity and Akt pathway.•NISC-6 induced apoptotic cell death and inhibited melanoma xenograft tumor growth.Synthesis and anti-melanoma activity of novel naphthalimide isoselenocyanate (NISC) and naphthalimide selenourea (NSU) analogs are described. The novel agents were screened for growth inhibition of different human melanoma cell lines including those having BRAFV600E mutation (UACC903, 1205Lu, and A375M) and BRAFWT (CHL-1). In general, the NISC analogs (4a-d) were more effective in inhibiting the cell viability than the NSU analogs (7a-b). Overall, NISC-6 (4d), having a six-carbon alkyl chain, was identified as the most cytotoxic compound in both BRAFV600E mutated and BRAFWT cells. NISC-6 docked strongly into the binding sites of Akt1 and human topoisomerase IIα (Topo-IIα), and the docking results were supported by experimental findings showing NISC-6 to inhibit of both Akt pathway and Topo-IIα activity in a dose dependent manner. Furthermore, NISC-6 effectively induced apoptosis in human melanoma cells, inhibited tumor growth by ∼69% in a melanoma mouse xenograft model, and showed excellent compliance with the Lipinski’ rule of five, suggesting both its efficacy and drug-like behavior under physiological conditions.Download high-res image (243KB)Download full-size image

The synthesis and anticancer evaluation of novel selenium-nonsteroidal anti-inflammatory drug (Se-NSAID) hybrid molecules are reported. The Se-aspirin analogue 8 was identified as the most effective agent in reducing the viability of different cancer cell lines, particularly colorectal cancer (CRC) cells, was more selective toward cancer cells than normal cells, and was >10 times more potent than 5-FU, the current therapy for CRC. Compound 8 inhibits CRC growth via the inhibition of the cell cycle in G1 and G2/M phases and reduces the cell cycle markers like cyclin E1 and B1 in a dose dependent manner; the inhibition of the cell cycle may be dependent on the ability of 8 to induce p21 expression. Furthermore, 8 induces apoptosis by activating caspase 3/7 and PARP cleavage, and its longer exposure causes increase in intracellular ROS levels in CRC cells. Taken together, 8 has the potential to be developed further as a chemotherapeutic agent for CRC.

•A series of 20 novel selenourea and thiourea derivatives was synthesized.•Compounds were tested against a panel of six human cancer cell lines.•The selenourea derivatives showed lower IC50 than the sulfur-containing analogs.•IC50 values for 1g were below 7.0 μM in all the cell lines and time points tested.•1g induced apoptosis by modulation of Caspases and anti-apoptotic proteins.A series of novel selenourea derivatives and corresponding thiourea analogs were synthesized and tested against a panel of six human cancer cell lines: melanoma (1205Lu), lung carcinoma (A549), prostatic carcinoma (DU145), colorectal carcinoma (HCT116), pancreatic epithelioid carcinoma (PANC-1) and pancreatic adenocarcinoma (BxPC3). In general, we found that the selenium-containing derivatives were more potent than their isosteric sulfur analogs. Four selenourea derivatives (1e, 1f, 1g and 1i) showed IC50 values below 10 μM in all of tested cell lines at 72 h. On the basis of its potent activity, compound 1g was selected for further biological evaluation in different colon cancer cell lines. Our results indicated that compound 1g induced apoptosis by caspase activation, along with inhibition of anti-apoptotic proteins.

Sphingosine kinase (SphK) is an oncogenic lipid kinase that regulates the sphingolipid metabolic pathway that has been shown to play a role in numerous hyperproliferative/inflammatory diseases. The SphK isoforms (SphK1 and SphK2) catalyze the conversion of the proapoptotic substrate d-erythrosphingosine to the promitogenic/migratory product sphingosine 1-phosphate (S1P). Accumulation of S1P has been linked to the development/progression of cancer and various other diseases including, but not limited to, asthma, inflammatory bowel disease, rheumatoid arthritis, and diabetic nephropathy. SphK therefore represents a potential new target for developing novel therapeutics for cancer and other diseases. This finding has stimulated the development and evaluation of numerous SphK inhibitors over the past decade or so. In this review, we highlight the recent advancement in the field of SphK inhibitors including SphK1 and SphK2 specific inhibitors. Both sphingolipid based and nolipidic small molecule inhibitors and their importance in treatment of cancer and other diseases are discussed.

Synthesis and anti-melanoma activity of various naphthalimide analogs, rationally modified by introducing isothiocyanate (ITC) and thiourea (TU) functionalities, found in well-known anti-cancer agents, is described. The structure–activity relationship comparison of the novel agents in inhibiting cancer cell growth was evaluated in various melanoma cell lines. Both ITC and TU analogs effectively inhibited cell viability and induced apoptosis in various human melanoma cells. Nitro substitution and increase in alkyl chain length, in general, enhanced the apoptotic activity of ITC derivatives. All the new compounds were well tolerated when injected intraperitoneal (i.p.) in mice at effective doses at which both the ITC and TU derivatives inhibited melanoma tumor growth in mice following i.p. xenograft. The nitro substituted naphthalimide–ITC derivative 3d was found to be the most effective in inducing apoptosis, and in inhibiting melanoma cell and tumor growth.Highlights► Naphthalimide analogs with isothiocyanate and thiourea functions are reported. ► Increase in alkyl chain length and nitro substitution enhanced the potency. ► Six carbon alkyl chain compound 3c and nitro substituted 3d were most cytotoxic. ► Compounds 3c and 3d were most effective in inducing apoptosis in melanoma cells. ► Compounds 3c and 3d inhibited melanoma tumor growth without any systemic toxicity.

O2-[4-(3-Pyridyl)-4-oxobut-1-yl]thymidine (O2-POB-dThd) is the most persistent adduct detected in the lung and liver of rats treated with tobacco specific nitrosamines: N′-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). It is an important biomarker to assess the human exposure to these carcinogens. The only synthetic method reported for O2-POB-dThd requires repeated HPLC purifications and could only be used to prepare an analytical standard due to very low yield (0.4%). We have developed for the first time a regioselective and efficient method for the total synthesis of O2-POB-dThd and its site-specifically adducted oligonucleotides. The main step in the synthesis of O2-POB-dThd was achieved by a novel method. The treatment of O2-5′-anhydrothymidine with the sodium salt of 4-(1,3-dithian-2-yl)-4-(3-pyridyl)butan-1-ol gave exclusively the O2-alkylated adduct, which was deprotected in one step to furnish the desired O2-POB-dThd in excellent yield. The product was characterized by NMR (1H and 13C), high-resolution MS, and HPLC analysis. This work provided for the first time a reliable method for large scale total synthesis of O2-POB-dThd that allowed for solid state site-specifically adducted oligomer synthesis. The O2-POB-dThd was converted to its phosphoramidite and subsequently used for the synthesis of oligodeoxynucleotides by standard methods. The oligomers were characterized by MS and HPLC analysis. These oligomers will facilitate the elucidation of the mutagenic potential of the O2-POB-dThd adduct, which will provide further insight into the role of tobacco-specific nitrosamines in inducing cancers in smokers.

Sphingosine kinase (SphK) is a lipid kinase with oncogenic activity, and SphK inhibitors (SKIs) are known for their anti-cancer activity. Here, we report highly efficient syntheses of SKIs and their aspirinyl (Asp) analogs. Both SKIs and their Asp analogs were highly cytotoxic towards multiple human cancer cell lines; in several cases the Asp analogs were up to three times more effective. Furthermore, they were equally potent inhibitors of SphK. The pharmacokinetic study indicated that SKI-I-Asp cleaved efficiently to form SKI-I and the half-life of SKI-I was increased from ∼7 h in SKI-I to ∼10 h in SKI-I-Asp injected mice, thereby prolonging its effect. In summary, the Asp-conjugated SKIs seem to be promising prodrugs of SKIs where delivery in vivo remains a problem.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear hormone receptor superfamily. Herein, we describe an efficient synthesis of a novel isosteric selenium analog of the highly specific PPARβ/δ ligand 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxy-acetic acid (GW501516; 1). The study examined the efficiency of the novel selenium analog 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-selenazol-5-yl)-methylsulfanyl)phenoxy-acetic acid (2) to activate PPARβ/δ and the effect of ligand activation of PPARβ/δ on cell proliferation and target gene expression in human HaCaT keratinocytes. The results showed that similar to GW501516, the Se-analog 2 increased expression of the known PPARβ/δ target gene angiopoietin-like protein 4 (ANGPTL4); the compound 2 was comparable in efficacy as compared to GW501516. Consistent with a large body of evidence, the Se-analog inhibited cell proliferation in HaCaT keratinocytes similar to that observed with GW501516. In summary, the novel Se-analog 2 has been developed as a potent PPARβ/δ ligand that may possess additional anti-cancer properties of selenium.

Synthesis and identification of novel phenylalkyl isoselenocyanates (ISCs), isosteric selenium analogues of naturally occurring phenylalkyl isothiocyanates (ITCs), as effective cytotoxic and antitumor agents are described. The structure−activity relationship comparison of ISCs with ITCs and effect of the increasing alkyl chain length in inhibiting cancer cell growth were evaluated on melanoma, prostate, breast, glioblastoma, sarcoma, and colon cancer cell lines. IC50 values for ISC compounds were generally lower than their corresponding ITC analogues. Similarly, in UACC 903 human melanoma cells, the inhibition of cell proliferation and induction of apoptosis were more pronounced with ISCs compared to ITCs. Further, ISCs and ITCs effectively inhibited melanoma tumor growth in mice following intraperitoneal xenograft. A similar reduction in tumor size was observed at 3 times lower doses of ISCs compared to corresponding ITCs.

Naphtho[8,1,2-ghi]chrysene, commonly known as naphtho[1,2-e]pyrene (N[1,2-e]P) is a widespread environmental pollutant, identified in coal tar extract, air borne particulate matter, marine sediment, cigarette smoke condensate, and vehicle exhaust. Herein, we determined the ability of rat liver microsomes to metabolize N[1,2-e]P and an unequivocal assignment of the metabolites by comparing them with independently synthesized standards. We developed the synthesis of both the fjord region and the K-region dihydrodiols and various phenolic derivatives for metabolite identification. The 12-OH-N[1,2-e]P, fjord region dihydrodiol 14 and diol epoxide 15 were synthesized using a Suzuki cross-coupling reaction followed by the appropriate manipulation of the functional groups. The K-region trans-4,5-dihydrodiol (18) was prepared by the treatment of N[1,2-e]P with OsO4 to give cis-dihydrodiol 16, followed by pyridinium chlorochromate oxidation to quinone 17, and finally reduction with NaBH4 to afford the dihydrodiol 18 with the desired trans stereochemistry. The 9-OH-N[1,2-e]P (30) and N[1,2-e]P trans-9,10-dihydrodiol (32) were also synthesized following a Suzuki cross-coupling approach starting from 1,2,3,6,7,8-hexahydropyrene-4-boronic acid. The metabolism of N[1,2-e]P with rat liver microsomes led to several dihydrodiol and phenolic metabolites as assessed by the HPLC trace. The 11,12-dihydrodiol and 4,5-dihydrodiol were identified as major dihydrodiol metabolites. The synthesized 9,10-dihydrodiol, on the other hand, did not match with any of the peaks in the metabolism trace. Among the phenols, only 12-OH-N[1,2-e]P was identified in the metabolism. The other phenolic derivatives synthesized, that is, the 4-/5-, 9-, 10-, and 11-hydroxy derivatives, were not detected in the metabolism trace. In summary, N[1,2-e]P trans-11,12-dihydrodiol was the major metabolite formed along with N[1,2-e]P 4̅,5-trans-dihydrodiol and 12-OH-N[1,2-e]P on exposure of rat liver microsomes to N[1,2-e]P. The presence of N[1,2-e]P in the environment and formation of fjord region dihydrodiol 14 as a major metabolite in in vitro metabolism studies strongly suggest the role of N[1,2-e]P as a potential health hazard.