INVESTIGATION OF ASYMMETRIC PLATINUM (IV) COMPLEXES AS ANTICANCER PRODRUGS

Ph.DDOCTOR OF PHILOSOPH

Biosynthesis and Biomimetic Synthesis of Flavonoid Diels-Alder Natural Products

This chapter describes the biosynthesis and biomimetic synthesis of naturally occurring flavonoid Diels‐Alder adducts found either from the family Moraceae or Zingiberaceae. The main topics addressed are biosynthetic studies by employing Morus alba L. cell cultures through feeding experiments of various exogenous substrates and putative precursors, as well as a various biomimetic approach for the chemical syntheses of flavonoid Diels‐Alder natural products

Pheophorbide b ethyl ester from a chlorella vulgaris dietary supplement

In the title compound, C37H38N4O6, four five-membered nitro­gen-bearing rings are nearly coplanar. Two N atoms in two these five-membered rings have attached H atoms, which contribute to the formation of intra­molecular N—H⋯N hydrogen bonds [N⋯N = 2.713 (5)–3.033 (6) Å]

Indoleninyl-substituted pyrimido[1,2-b]indazoles via a facile condensation reaction

A new series of pyrimido[1,2-b]indazoles bearing indolenine moieties was synthesized through a simple condensation reaction with up to 94% yield. The present method features the versatile formation of a pyrimidine ring with a broad range of substrates, great functional group compatibility and facile synthetic operation. The work offers opportunities in drug development as well as in materials scienc

Design of New Competitive Dengue Ns2b/Ns3 Protease Inhibitors—A Computational Approach

Dengue is a serious disease which has become a global health burden in the last decade. Currently, there are no approved vaccines or antiviral therapies to combat the disease. The increasing spread and severity of the dengue virus infection emphasizes the importance of drug discovery strategies that could efficiently and cost-effectively identify antiviral drug leads for development into potent drugs. To this effect, several computational approaches were applied in this work. Initially molecular docking studies of reference ligands to the DEN2 NS2B/NS3 serine protease were carried out. These reference ligands consist of reported competitive inhibitors extracted from Boesenbergia rotunda (i.e., 4-hydroxypanduratin A and panduratin A) and three other synthesized panduratin A derivative compounds (i.e., 246DA, 2446DA and 20H46DA). The design of new lead inhibitors was carried out in two stages. In the first stage, the enzyme complexed to the reference ligands was minimized and their complexation energies (i.e., sum of interaction energy and binding energy) were computed. New compounds as potential dengue inhibitors were then designed by putting various substituents successively on the benzyl ring A of the reference molecule. These substituted benzyl compounds were then computed for their enzyme-ligand complexation energies. New enzyme-ligand complexes, exhibiting the lowest complexation energies and closest to the computed energy for the reference compounds, were then chosen for the next stage manipulation and design, which involved substituting positions 4 and 5 of the benzyl ring A (positions 3 and 4 for 2446DA) with various substituents

Supramolecular assembly and spectroscopic characterization of indolenine–barbituric acid zwitterions

A series of indolenine and barbituric acid zwitterion scaffolds were synthesized with a maximum yield of 98% via the formation of C–C single bond. The structures were unambiguously elucidated by various spectroscopic techniques such as 1H, 13C NMR (1D, 2D), FT-IR and high-resolution mass spectrometry (HRMS). Single crystal X-ray crystallography analysis on 22, as the 22.DMF 1:1 solvate, confirms the presence of wellseparated iminium and enolate centres, and also confirms that the BA ring is highly twisted with respect to the indolenine ring due to steric hindrance. The presence of N–H∙∙∙O and N–H∙∙∙O- groups favour a 1D-supramolecular assembly in the solid-state. The orange or yellow solutions of the zwitterion exhibit an intense molar absorption coefficient, ε ranging between 0.21 × 104 and 2.93 × 104 M-1 cm-1 in the UV-vis region. Furthermore, the Intramolecular Charge Transfer (ICT) peak of zwitterion displays a hypsochromic shift in absorption behavior when the polarity of the solvent increases. Moreover, treatment of small amount of trifluoroacetic acid (TFA) to the DMF solution of 19 resulted in the protonation of an enolate of BA ring. This fundamental work provides valuable structural design and information for the construction of supramolecular chemistry and synthetic dyes based on indolenine substituted BA derivatives

Mindfulness-based supportive therapy on reducing suffering in patients with advanced cancer: randomised controlled trial

Objectives Suffering is common among patients with advanced cancer. The practice of mindfulness during patient care can potentially reduce suffering. We aimed to examine the efficacy of mindfulness-based supportive therapy (MBST) on reducing suffering in patients with advanced cancer. Methods We conducted a parallel-group, single-blinded, randomised controlled trial at the University of Malaya Medical Centre, Malaysia. Seventy-three patients with advanced cancer with an overall suffering score ≥4/10 based on the Suffering Pictogram were recruited and randomly assigned into either the MBST group (n=34) or the control group (n=39). Results There was a statistically significant reduction in the overall suffering score in the MBST group compared with the control group (U=432.5, median1 =−2.0, median2 =−1.0, z=−2.645, p=0.008). There was also significant improvement in the total Hospital Anxiety and Depression Scale score (U=483.5, median1 =−4.0, median2 =−3.0, z=−1.994, p=0.046), and the total Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being score (U=252.0, median1 =+14.5, median2 =+5.0, z=−4.549, p=0.000) in the MBST group compared with the control group. Conclusions The results provided evidence that the practice of MBST during patient care could promote positive psychosocial outcome

Diameter-dependent release of a cisplatin pro-drug from small and large functionalized carbon nanotubes

The use of platinum-based chemotherapeutic drugs in cancer therapy still suffers from severe disadvantages, such as lack of appropriate selectivity for tumor tissues and insurgence of multi-drug resistance. Moreover, drug efficacy can be attenuated by several mechanisms such as premature drug inactivation, reduced drug uptake inside cells and increased drug efflux once internalized. The use of functionalized carbon nanotubes (CNTs) as chemotherapeutic drug delivery systems is a promising strategy to overcome such limitations due to their ability to enhance cellular internalization of poorly permeable drugs and thus increase the drug bioavailability at the diseased site, compared to the free drug. Furthermore, the possibility to encapsulate agents in the nanotubes’ inner cavity can protect the drug from early inactivation and their external functionalizable surface is useful for selective targeting. In this study, a hydrophobic platinum(IV) complex was encapsulated within the inner space of two different diameter functionalized multi-walled CNTs (Pt(IV)@CNTs). The behavior of the complexes, compared to the free drug, was investigated on both HeLa human cancer cells and RAW 264.7 murine macrophages. Both CNT samples efficiently induced cell death in HeLa cancer cells 72 hours after the end of exposure to CNTs. Although the larger diameter CNTs were more cytotoxic on HeLa cells compared to both the free drug and the smaller diameter nanotubes, the latter allowed a prolonged release of the encapsulated drug, thus increasing its anticancer efficacy. In contrast, both Pt(IV)@CNT constructs were poorly cytotoxic on macrophages and induced negligible cell activation and no pro-inflammatory cytokine production. Both CNT samples were efficiently internalized by the two types of cells, as demonstrated by transmission electron microscopy observations and flow cytometry analysis. Finally, the platinum levels found in the cells after Pt(IV)@CNT exposure demonstrate that they can promote drug accumulation inside cells in comparison with treatment with the free complex. To conclude, our study shows that CNTs are promising nanocarriers to improve the accumulation of a chemotherapeutic drug and its slow release inside tumor cells, by tuning the CNT diameter, without inducing a high inflammatory response

Efficient one-pot synthesis of 2,2-dimethyl-2H-chromenes via pd(II)-catalyzed coupling and SiO2-promoted condensation of o-halophenols with 2-methyl-3-buten-2-ol

An efficient synthesis of 2,2-dimethyl-2H-chromenes was accomplished by Pd(II)-catalyzed coupling and SiO2-promoted condensation of o-halophenols with 2-methyl-3-buten-2-ol (1,1-dimethylallyl alcohol) in one pot. The method is very general and can be useful for the synthesis of some natural 2,2-dimethyl-2H-chromenes

An efficient synthesis of (+/-)-panduratin A and (+/-)-isopanduratin A, inhibitors of dengue-2 viral activity

Panduratin A and its regioisomer isopanduratin A are synthesized in four steps from (E)-ocimene, [(E)-3,7-dimethyl-1,3,6-octatriene] via a Diels-Alder cycloaddition reaction. (C) 2009 Elsevier Ltd. All rights reserved