The first section of this work describes the synthesis of a library of novel rhein analogues that are potential anticancer agents. The design of these compounds takes advantage of the ability for rhein to intercalate into DNA and as the incorporation of an alkylating agent, which serves to covalently modify DNA. In three cell lines, these compounds showed potent cytotoxicity with IC50 in the low to mid-μM range. The second project was focused on the development of an efficient synthesis of 6H-Isoindolo[2,1-α]indol-6-one (24), a core structure for a number of biologically active compounds. The approach is metal-free and uses a Beckmann rearrangement followed by an intramolecular cyclization.

Cancer is responsible for one fourth of the total deaths and is the second leading cause of death, behind heart disease, in the United States. However, there are as many approaches to curing cancer as there are types of cancer. One important issue in solid tumors is hypoxia, a lack of oxygen, which promotes angiogenesis and anaerobic metabolism, which can increase cancer progression and metastasis. The HIF transcription factor is responsible for the mediation of many processes involved during hypoxia and is linked to poor patient prognosis, increased cancer progression, and invasiveness of tumors. With this in mind, the HIF pathway has become an attractive target for small molecule inhibition. Herein, we describe the design and synthesis of small molecules that inhibit the HIF pathway. These compounds are based off an initial “hit” compound, KCN-1, from screening of a 10,000 compound library. KCN1 is both highly effective and has a low toxicity profile. Over 200 compounds have been synthesized by the Wang lab, with the best compound IVSR64b having an IC50 of 0.28 μM. Of special interest is that these compounds do not appear to have any inherent toxicity toward healthy tissues, but only affect cancer cells. Moreover, x-ray crystal structures for both KCN-1 and IVSR64b were obtained and used as the basis for computational modeling, which is still in progress.

Understanding the influence of environment and correlation/relationships among traits is necessary in selection for crop quality improvement. Therefore, correlations among antioxidant activity (AOA), total phenolics (TP), phenolic composition, and specific gravity (SPG) in four potato (Solanum tuberosum, L.) cultivars (Atlantic, Red La Soda, Russet Norkotah, and Yukon Gold) grown in nine states (California, Idaho, Michigan, Minnesota, New Jersey, North Carolina, Oregon, Texas, and Wisconsin) for three years, and in 15 advanced selections grown in Texas were investigated. Cultivars within and between locations were significantly different in AOA, TP, and SPG. Significant effects of cultivar, year, location and their interactions on AOA, TP, and SPG were observed. There were significant positive correlations among the four cultivars between AOA and TP, and negative correlations between AOA and SPG, and between TP and SPG. However, correlations between AOA and SPG, and between TP and SPG, in the advanced selections were not significant. Some tuber-bearing wild potato species were higher in AOA and TP than the commercial cultivars; therefore, they could be used as parental material in breeding for high AOA and TP. However, use of wild species that might be higher in total glycoalkaloids (TGA) than cultivars could result in progenies with high TGA if the traits are positively correlated. To elucidate the relationships among AOA, TP and TGA, accessions of Solanum jamesii and S. microdontum from the US Potato Genebank were screened for these traits and their correlations determined. Also, anti-proliferative and cytotoxic effects of 15 S. jamesii tuber extracts (5 and 10 μg/ml) on human prostate (LNCaP) and colon (HT-29) cancer cells was determined in vitro. Alpha-solanine and α-chaconine were found in both species, while tomatine and dehydrotomatine were quantified in some S. microdontum accessions. Both species were higher in all above traits than the Atlantic, Red La Soda, and Yukon Gold cultivars. More than 90% of S. jamesii accessions had TGA levels < 20 mg/100g fresh weight, while only two accessions of S. microdontum, P1 500041 and PI 473171, exhibited TGA < 20 mg/100g. Neither AOA nor TP was significantly correlated with TGA in both species. Also, individual phenolics were not correlated with TGA. Solanum jamesii accessions significantly reduced proliferation of HT-29 (5 and 10μg/ml) and LNCaP (10μg/ml) cells and were not cytotoxic compared to the control (DMSO). Therefore, since AOA and TP were not found to be correlated with TGA, using wild accessions in breeding for increased health promoting compounds would not necessarily increase glycoalkaloids in newly developed potato cultivars.

No description available.

No description available.

Several temporarily stable polymer micelle systems that might be used as ultrasonic-activated drug delivery carriers were synthesized and investigated. These polymeric micelle systems were Plurogel®, Tetronic®, poly(ethylene oxide)-b-poly(N-isopropylacrylamide) and poly(ethylene oxide)-b-poly(N-isopropylacrylamide-co-2-hydroxyethyl methacrylate-lactaten). In previous work in our lab, Pruitt et al. developed a stabilized drug carrier named Plurogel® [5, 6]. Unfortunately, the rate of the successful Plurogel® synthesis was only about 30% by simply following Pruitt's process. In this work, this rate was improved to 60% by combining the process of adding 0.15 M NaCl and/or 10 µl/ml n-butanol and by preheating the solution before polymerization. Tetronics® were proved not to be good candidates to form temporarily stable polymeric micelle system by polymerizing interpenetrating networks inside their micelle cores. Tetronic micelle systems treated by this process still were not stable at concentrations below their critical micelle concentration (CMC). Poly(ethylene oxide)-b-poly(N-isopropylacrylamide)-N,N-bis(acryloyl)cystamine micelle-like nanoparticles were developed and characterized. When the N,N-bis(acryloyl)cystamine (BAC) was from 0.2 wt% to 0.75 wt% of the mass of poly(N-isopropylacrylamide), diameters of the nanoparticles at 40ºC were less than 150 nm. The cores of the nanoparticles were hydrophobic enough to sequester 1,6-diphenylhexatriene (DPH) and the anti-cancer drug doxorubicin (DOX). Nanoparticles with 0.5 wt% BAC stored at room temperature in 0.002 mg/ml solutions were stable for up to two weeks. Poly(ethylene oxide)-b-poly(N-isopropylacrylamide-co-2-hydroxyethyl methacrylate-lactaten) micelle systems were synthesized and characterized. The degree of polymerization of lactate side group, n, was 3 or 5. The copolymers with N-isopropylacrylamide:2-hydroxyethyl methacrylate-lactate3: poly(ethylene oxide) (NIPAAm:HEMA-lactate3:PEO) ratios of 20.0:5.0:1 or 22.5:2.5:1 and with NIPAAm:HEMA-lactate5:PEO ratios of 17.5:7.5:1, 20.0:5.0:1 or 22.5:2.5:1 produced micelles stable about 2 days at 40°C. The cores of the micelles were hydrophobic enough to sequester DPH and DOX. The DOX release from the micelles having molar ratio of NIPAAm:HEMA-lactate3:PEO equal to 20.0:5.0:1 was about 2 % at room temperature and 4 % at body temperature. This system is a possible candidate for ultrasonically activated drug delivery.

No description available.

Yes / A library of new bis-picolinamide ruthenium(III) dihalide complexes of the type RuX2L2 (X = Cl or I and L = picolinamide) have been synthesised and characterised. They exhibit different picolinamide ligand binding modes, whereby one ligand is bound (N,N) and the other bound (N,O). Structural studies reveal a mixture of cis and trans isomers for the RuCl2L2 complexes but upon a halide exchange reaction to RuI2L2, only single trans isomers are present. High cytotoxic activity against human cancer cell lines was observed, with potencies for some complexes similar to or better than cisplatin. Conversion to RuI2L2 substantially increased activity towards cancer cell lines by >12-fold. The RuI2L2 complexes displayed potent activity against the A2780cis (cisplatin-resistant human ovarian cancer) cell line, with >4-fold higher potency than cisplatin. Equitoxic activity was observed against normoxic and hypoxic cancer cells, indicating the potential to eradicate both the hypoxic and aerobic fractions of solid tumours with similar efficiency. Selected complexes were also tested against non-cancer ARPE-19 cells. The RuI2L2 complexes are more potent than the RuCl2L2 analogues, and also more selective towards cancer cells with a selectivity factor >7-fold.

No / Telomerase-targeted strategies have aroused recent interest in anti-cancer chemotherapy, because DNA-binding drugs can interact with high-order tetraplex rather than double-stranded (duplex) DNA targets in tumour cells. However, the protracted cell-drug exposure times necessary for clinical application require that telomerase inhibitory efficacy must be accompanied by both low inherent cytotoxicity and the absence of mutagenicity/genotoxicity. For the first time, the genotoxicity of a number of structurally diverse DNA-interactive telomerase inhibitors is examined in the Ames test using six Salmonella typhimurium bacterial strains (TA1535, TA1537, TA1538, TA98, TA100, and TA102). DNA damage induced by each agent was also assessed using the Comet assay with human lymphocytes. The two assay procedures revealed markedly different genotoxicity profiles that are likely to reflect differences in metabolism and/or DNA repair between bacterial and mammalian cells. The mutational spectrum for a biologically active fluorenone derivative, shown to be mutagenic in the TA100 strain, was characterised using a novel and rapid assay method based upon PCR amplification of a fragment of the hisG46 allele, followed by RFLP analysis. Preliminary analysis indicates that the majority (84%) of mutations induced by this compound are C→A transversions at position 2 of the missense proline codon of the hisG46 allele. However, despite its genotoxic bacterial profile, this fluorenone agent gave a negative response in the Comet assay, and demonstrates how unwanted systemic effects (e.g., cytotoxicity and genotoxicity) can be prevented or ameliorated through suitable molecular fine-tuning of a candidate drug in targeted human tumour cells. / CAEB, Balearic Islands and Yorkshire Cancer Research

Yes / Silane-substituted imidazotetrazines 1,2 were investigated for their activity as anticancer prodrugs related to temozolomide (TMZ). The TMS-derivative 1 showed an activity profile against TMZ susceptible and resistant cell lines very similar to TMZ; in contrast, the SEM-derivative 2 showed activity irrespective of MGMT expression or MMR deficiency (Table). Probing the prodrug activation mechanism by NMR kinetic studies determined that the TMS compound 1 follows a reaction pathway and time-course very similar to temozolomide. 1H-NMR spectra of the reaction mixture showed considerable incorporation of deuterium into the final alkylation products of the reaction (methanol and methyl phosphate) as had previously been shown for temozolomide (Wheelhouse, R.T., et al. Chem. Commun. 1993, 15, 1177–1178). The SEM-derivative 2 reacted more rapidly than TMZ or TMS-derivative 1. Somewhat surprisingly, the silane remained intact throughout the experiment and the observed reaction was the hydrolysis of the imidazo-tetrazine to ultimately release formaldehyde hydrate and 2-TMS-ethanol. In conclusion, TMS-derivative 1 is a diazomethane precursor with prodrug activation mechanism, kinetics and anti-cancer activity in vitro similar to TMZ. In contrast, the SEM derivative 2 was more rapidly hydrolysed, a precursor of 2-TMS-ethanol and had activity in vitro different from TMZ. 2-TMS-ethanol was previously reported as a non-toxic compound in mice (Voronkov, M.G., et al. Dokl. Akad. Nauk SSSR 1976, 229, 1011–1013) and is known as a substrate for alcohol dehydrogenase (Zong, M.-H., et al. Appl. Microbiol. Biotechnol. 1991, 36, 40–43) and as a modest inhibitor of acetylcholinesterase (Aberman, A., et al. Biochim. Biophys. Acta 1984, 791, 278–280; Cohen, S.G., et al. J. Med. Chem. 1985, 28, 1309–1313).