Through the ICBG (International Cooperative Biodiversity Group) program and a continuing search for anticancer compounds, plant extracts were obtianed from Suriname and Madagascar and screened for cytotoxic activity in the A2780 human ovarian cancer cell line. Fractionation of a leaf and flower extract of Casearia nigrescens led to the isolation of six new clerodane diterpenes. Four were new natural products and the other two were previously unreported hydrolysis products. Their structures were determined using mass spectrometry and 1-D and 2-D NMR. All six compounds were cytotoxic in the A2780 human ovarian cancer cell line. Fractionation of a leaf extract of Vernonia pachyclada led to the isolation of four new sesquiterpene lactones. Their structures were determined using mass spectrometry, 1-D and 2-D NMR, and (in one case) single crystal X-ray diffraction. All four compounds were cytotoxic in the A2780 human ovarian cancer cell line. Fractionation of an extract of Casimirella ampla led to the isolation of three new diterpenes and two known diterpenes. Their structures were determined using mass spectrometry and 1-D and 2-D NMR. All five compounds were cytotoxic in the A2780 human ovarian cancer cell line. Fractionation of root and stem extracts of Mendoncia cowanii led to the isolation of two new naphthaquinones, and two known naphthaquinones. Their structures were determined using mass spectrometry and 1-D and 2-D NMR. All four compounds were cytotoxic in the A2780 human ovarian cancer cell line and three compounds exhibited weak inhibition of Akt kinase. The fractionation of five additional extracts resulted in the isolation of twelve known compounds. Their structures were determined using mass spectrometry, 1-D and 2-D NMR, and comparison to literature data. All twelve compounds were cytotoxic in the A2780 human ovarian cancer cell line. / Ph. D.

In our continuing search for biologically active natural products from Madagascar as part of an International Cooperative Biodiversity Group (ICBG) program, a total of four antiproliferative extracts were studied, leading to the isolation of twelve novel compounds with antiproliferative activity against the A2780 human ovarian cancer line, and one extract with antimalarial activities was studied, which led to the isolation of five new natural products with antimalarial activities against the Dd2 and HB3 malarial parasites. The plants and their metabolites are discussed in the following order: one new xanthone and two known guttiferones from Symphonia tanalensis Jum. & H. Perrier (Clusiaceae); four new diphenyl propanes and one new cyclohepta-dibenzofuran skeleton from Bussea sakalava (Fabaceae); four new cardiac glycosides from Leptadenia madagascariensis Decne. (Apocynaceae); two new and four known alkaloids from Ambavia gerrardii (Baill.) Le Thomas (Annonaceae); five new sesquiterpene lactones from Polycline proteiformis Humbert (Asteraceae). The structures of all compounds were determined by analysis of their mass spectrometric, 1D and 2D NMR, UV and IR spectroscopic and optical rotation data. Other than structure elucidation, this dissertation also involve bioactivity evaluation of all the isolates, synthesis of two interesting alkaloids, as well as a proposal for the possible biosynthetic pathway of the new cyclohepta-dibenzofuran skeleton. / Ph. D.

Paclitaxel is one of the most successful anti-cancer drugs, particularly in the treatment of breast cancer and ovarian cancer. For the investigation of the interaction between paclitaxel and MD-2 protein, and development of new antagonists for lipopolysaccharide, several C10 A-nor-paclitaxel analogs have been synthesized and their biological activities have been evaluated. In order to reduce the myelosuppression effect of the paclitaxel, several C3â ² and C4 paclitaxel analogs have been synthesized and their biological evaluation have been studied. / Master of Science

No / PURPOSE: C-1311 is a member of the novel imidazoacridinone family of anticancer agents. This phase 1 trial was designed to investigate the safety, tolerability and preliminary anti-tumour activity of C-1311. PATIENTS AND METHODS: This was a phase 1, inter-subject dose escalating and pharmacokinetic study of intravenous (IV) C-1311, administered weekly during 3consecutive weeks followed by 1week rest (constituting 1 cycle) in subjects with advanced solid tumours. RESULTS: Twenty-two (22) patients were treated with C-1311, the highest dose given was 640mg/m(2). All subjects experienced one or more treatment-related adverse events (AEs). The most frequently observed treatment-related AEs were neutropaenia and nausea (50% each), followed by vomiting (27%), anaemia (23%), asthenia (23%) and diarrhoea (18%). Most treatment-related AEs were of Common Terminology Criteria for Adverse Events (CTCAE) grades 1-2, except for the blood and lymphatic system disorders, which were primarily of grades 3-4. The recommended dose (RD) of C-1311 administered as once weekly IV infusions for 3weeks every 4weeks is 480mg/m(2), with the dose limiting toxicity (DLT) being grade 4 neutropaenia lasting more than 7days. Treatment at this dose offers a predictable safety profile and excellent tolerability. CONCLUSION: The safety profile and preliminary anti-tumour efficacy of C-1311, observed in this broad-phase dose-finding study, warrants further evaluation of the compound.

No / The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a class of DNA minor groove binding agents that react covalently with guanine bases, preferably at Pu-G-Pu sites. A series of three fluorescent PBD¿coumarin conjugates with different linker architectures has been synthesized to probe correlations between DNA binding affinity, cellular localization and cytotoxicity. The results show that the linker structure plays a critical role for all three parameters. Graphical abstract A series of three fluorescent PBD¿coumarin conjugates with different linker architectures has been synthesized to probe correlations between DNA-binding affinity, cellular localization and cytotoxicity.

No / Inadequate drug delivery to tumours is now recognised as a key factor that limits the efficacy of anticancer drugs. Extravasation and penetration of therapeutic agents through avascular tissue are critically important processes if sufficient drug is to be delivered to be therapeutic. The purpose of this study is to develop an in silico model that will simulate the transport of the clinically used cytotoxic drug doxorubicin across multicell layers (MCLs) in vitro. Three cell lines were employed: DLD1 (human colon carcinoma), MCF7 (human breast carcinoma) and NCI/ADR-Res (doxorubicin resistant and P-glycoprotein [Pgp] overexpressing ovarian cell line). Cells were cultured on transwell culture inserts to various thicknesses and doxorubicin at various concentrations (100 or 50 microM) was added to the top chamber. The concentration of drug appearing in the bottom chamber was determined as a function of time by HPLC-MS/MS. The rate of drug penetration was inversely proportional to the thickness of the MCL. The rate and extent of doxorubicin penetration was no different in the presence of NCI/ADR-Res cells expressing Pgp compared to MCF7 cells. A mathematical model based upon the premise that the transport of doxorubicin across cell membrane bilayers occurs by a passive "flip-flop" mechanism of the drug between two membrane leaflets was constructed. The mathematical model treats the transwell apparatus as a series of compartments and the MCL is treated as a series of cell layers, separated by small intercellular spaces. This model demonstrates good agreement between predicted and actual drug penetration in vitro and may be applied to the prediction of drug transport in vivo, potentially becoming a useful tool in the study of optimal chemotherapy regimes.

Yes / Enantiomers of a relatively rigid DNA-binding metallo-helix are shown to have comparable activity to that of cisplatin against the cell lines MCF7 (human breast adenocarcinoma) and A2780 (human ovarian carcinoma) but are ca five times more active against the cisplatin-resistant A2780cis. The cell-line HCT116 p53+/+ (human colon carcinoma) is highly sensitive giving IC50 values in the nM range, far lower than the cisplatin control. The hypothesis that the biological target of such metallohelices is DNA is probed by various techniques. Tertiary structure changes in ct-DNA (formation of loops and intramolecular coiling) on exposure to the compounds are demonstrated by atomic force microscopy and supported by circular/linear dichroism in solution. Selectivity for 50-CACATA and 50-CACTAT segments is shown by DNase I footprinting. Various three- and four-way oligonucleotide junctions are stabilised, and remarkably only the L metallo-helix enantiomer stabilizes T-shaped 3WJs during gel electrophoresis; this is despite the lack of a known helix binding site. In studies with oligonucleotide duplexes with bulges it is also shown for the first time that the metallo-helix binding strength and the number of binding sites are dependent on the size of the bulge. In contrast to all the above, flexible metallo-helices show little propensity for structured or selective DNA binding, and while for A2780 the cancer cell line cytotoxicity is retained the A2780cis strain shows significant resistance. For all compounds in the study, H2AX FACS assays on HCT116 p53+/+ showed that no significant DNA damage occurs. In contrast, cell cycle analysis shows that the DNA binders arrest cells in the G2/mitosis phase, and while all compounds cause apoptosis, the DNA binders have the greater effect. Taken together these screening and mechanistic results are consistent with the more rigid helices acting via a DNA binding mechanism while the flexible assemblies do not.

Yes / The complexes [RuCp*(PP)Cl] (Cp* = C5Me5; [1], PP = dppm; [4], PP = Xantphos), [RuCp#(PP)Cl] (Cp# = C5Me4(CH2)5OH; [2], PP = dppm; [5], PP = Xantphos) and [RuCp*(dppm)(CH3CN)][SbF6] [3] were synthesized and evaluated in vitro as anticancer agents. Compounds 1–3 gave nanomolar IC50 values against normoxic A2780 and HT-29 cell lines, and were also tested against hypoxic HT-29 cells, maintaining their high activity. Complex 3 yielded an IC50 value of 0.55 ± 0.03 μM under a 0.1% O2 concentration.

No / Aspirin, formally known as acetylsalicylic (ASA), is most widely used and cheapest over-the counter drugs. It is used not only for the common fevers, headaches and inflammation, but also for reducing the risk of heart attacks. In recent years, it is also linked to anti-cancer potential. Recently the US Preventive Services Working Group (UPSTF) release aspirin as a guide for cardiovascular disease and primary prevention of colorectal cancer. Platelets have been shown to play a crucial role in cancer metastasis for many years and are proposed to have an intimate reciprocal crosstalk with cancer cells. They may alter the properties of each other and have reciprocal effects. But the exact role of platelets in modifying the tumor cell properties has not been established. In clinical, cancer patients may receive platelets from outside to treat thrombocytopenia and bleeding induced by intensive chemotherapy. Therefore understanding the exact role of platelets in carcinogenesis always is a research interest, especially when evaluating anti-cancer drugs. In this study we exam the effect of platelets on viability, proliferation and adhesion of lung cancer cells A549 in culture conditions, using different concentrations of platelet rich plasma (PRP) with and without the presence of antiplatelet drug aspirin. The tumor cell EMT transformation was also investigated under different combination of PRP and aspirin in vitro. Our data showed that low-dose of aspirin can promote cell proliferation and high-dose of aspirin could inhibit cell proliferation. High concentrations of platelet-rich plasma can inhibit cell proliferation but low concentrations of platelet-rich plasma had no significant effect on cell proliferation. Platelet-rich plasma can gather around the cell to form a gelatinous film, and this lead us to a promoted tumor cell distant metastasis model. We further found out that the combination of aspirin and PRP could increase cell viability compared to single use of PRP and Aspirin can affect cell proliferation by inhibiting platelet effects. Platelet-rich plasma reduces the adhesion of A549 cell can be attenuated by aspirin. Further works will focus on combination of different doses of aspirin and PRP to confirm the above results. Other format of aspirin (nano-form) and other NSAID inflammatory drugs like Ibuprofen will also be tested. / Abstract of conference paper.

Yes / Platinum drugs are widely used for cancer treatment. Other precious metals are promising, but their clinical progress depends on achieving different mechanisms of action to overcome Pt-resistance. Here, we evaluate 13 organo-Os complexes: 16-electron sulfonyl-diamine catalysts [(η6-arene)Os(N,N′)], and 18-electron phenylazopyridine complexes [(η6-arene)Os(N,N’)Cl/I]+ (arene = p-cymene, biphenyl, or terphenyl). Their antiproliferative activity does not depend on p21 or p53 status, unlike cisplatin, and their selective potency toward cancer cells involves the generation of reactive oxygen species. Evidence of such a mechanism of action has been found both in vitro and in vivo. This work appears to provide the first study of osmium complexes in the zebrafish model, which has been shown to closely model toxicity in humans. A fluorescent osmium complex, derived from a lead compound, was employed to confirm internalization of the complex, visualize in vivo distribution, and confirm colocalization with reactive oxygen species generated in zebrafish. / Wellcome Trust (grant no. 107691/Z/15/Z), ERC (grant nos. 247450, 324594), Science City (AWM and ERDF), WCPRS and Bruker Daltonics (Studentship for JPCC), Mike and Enfys Bagguley, and EPSRC (Studentship for HEB, and grant no. EP/F034210/1).