The synthesis and biological evaluation of novel analogues of isocryptolepine

This thesis investigates the potential of the alkaloid isocryptolepine 16 as a lead compound in antimalarial drug development. Fifteen derivatives of the parent alkaloid were prepared and fully characterised, twelve of which were novel compounds. A select group of compounds were subsequently evaluated for both antimalarial activity and cytotoxicity.Three previously reported synthetic methodologies to the parent alkaloid were initially investigated; wherein two approaches were able to be reproduced or improved. These two synthetic methodologies were subsequently applied to the preparation of derivatives. The first of these methodologies, the Jonckers Method, involved two consecutive palladium catalysed coupling reactions. During the course of these investigations it was found that these two reactions could be combined into a single ‘domino’ reaction resulting in a reduction in the number of steps required to prepare the parent alkaloid. This methodology was then applied to the preparation of both ring-substituted and structural isomers. The second methodology, The Molina Method, involved a benzotriazole-mediated strategy and was applicable to preparing isocryptolepine derivatives with ring substituents on the quinoline ring. Finally a method for selective electrophilic aromatic substitution was developed and applied to the preparation of a further range of halogenated derivatives.Eight of the prepared derivatives were selected for biological evaluation. Antimalarial activity was assessed against a chloroquine sensitive and resistant strain of P. falciparum, whilst cytotoxicity was evaluated against mouse embryonic fibroblasts (3T3 cells). All compounds were found to be more active compared to the parent alkaloid against the chloroquine resistant strain of P. falciparum; specifically 8-bromo-2-chloroisocryptolepine 107 (IC[subscript]50 = 85 nM) and 8-bromo-3-chloroisocryptolepine 105 (IC[subscript]50 = 100 nM) were the most potent. Cytotoxicity evaluations revealed that ring substitution did not enhance cytotoxicity and the most potent antimalarial derivative, 8-bromo-2-chloroisocryptolepine 107 (IC[subscript]50 = 9.01 μM), displayed a 4-fold reduction in cytotoxicity.In conclusion, isocryptolepine 16 and its derivatives have significant potential as antimalarial lead compounds, with many derivatives possessing enhanced bioactivity versus the parent. This study has also identified 8-bromo-2-chloroisocryptolepine 107 to be a very promising lead compound which warrants further biological or pharmaceutical investigation

Aluminum Borate Nanowires from the Pyrolysis of Polyaminoborane Precursors

Polyaminoboranes [N(R)H-BH2]n (1: R = H, 2: R = Me) were pyrolyzed on a range of substrates: silicon, metal foils (stainless steel, nickel, and rhodium), and sapphire wafers, as well as on Al2O3 and AlN powders.</p

An investigation into the hexagonal phases formed in high-concentration dispersions of well-defined cylindrical block copolymer micelles

<p>This paper presents a detailed analysis of the structure of the hexagonal phase of poly(ferrocenylsilane) (PFS)-based cylindrical micelles found at concentrations above ca. 5 wt. % in non-polar solvents such as decane. Small-angle X-ray scattering indicated that the hexagonal order is not long-range. In all samples, deviations in the lower order peak positions were observed with respect to those expected for a perfect hexagonal lattice, with the degree of deviation correlating with micelle length. Furthermore, analysis of the peak shapes and peak widths suggests that the phase possesses intermediate translational order similar. to the hexatic phase. The observed features can be reproduced by amending Hosemann’s paracrystal theory to include a distribution of lattice parameters to model well and poorly condensed regions. It is proposed that this distribution arises due to the bending and intertwining of individual micelles in a hexagonal lattice, resulting in a kinetically trapped phase that is initially neither perfectly hexagonal nor canonically hexatic but which anneals over time towards a perfect hexagonal lattice.</p

Polyferrocenylsilanes:synthesis, properties, and applications

This comprehensive review covers polyferrocenylsilanes (PFSs), a well-established, readily accessible class of main chain organosilicon metallopolymer. The focus is on the recent advances involving PFS homopolymers and block copolymers and the article covers the synthesis, properties, and applications of these fascinating materials.</p

Heavier alkaline‐earth catalyzed dehydrocoupling of silanes and alcohols for the synthesis of metallo‐polysilylethers

The dehydrocoupling of silanes and alcohols mediated by heavier alkaline-earth catalysts, [Ae{N(SiMe 3) 2} 2⋅(THF) 2] (I–III) and [Ae{CH(SiMe 3) 2} 2⋅(THF) 2], (IV–VI) (Ae=Ca, Sr, Ba) is described. Primary, secondary, and tertiary alcohols were coupled to phenylsilane or diphenylsilane, whereas tertiary silanes are less tolerant towards bulky substrates. Some control over reaction selectivity towards mono-, di-, or tri-substituted silylether products was achieved through alteration of reaction stoichiometry, conditions, and catalyst. The ferrocenyl silylether, FeCp(C 5H 4SiPh(OBn) 2) (2), was prepared and fully characterized from the ferrocenylsilane, FeCp(C 5H 4SiPhH 2) (1), and benzyl alcohol using barium catalysis. Stoichiometric experiments suggested a reaction manifold involving the formation of Ae–alkoxide and hydride species, and a series of dimeric Ae–alkoxides [(Ph 3CO)Ae(μ 2-OCPh 3)Ae(THF)] (3 a–c, Ae=Ca, Sr, Ba) were isolated and fully characterized. Mechanistic experiments suggested a complex reaction mechanism involving dimeric or polynuclear active species, whose kinetics are highly dependent on variables such as the identity and concentration of the precatalyst, silane, and alcohol. Turnover frequencies increase on descending Group 2 of the periodic table, with the barium precatalyst III displaying an apparent first-order dependence in both silane and alcohol, and an optimum catalyst loading of 3 mol % Ba, above which activity decreases. With precatalyst III in THF, ferrocene-containing poly- and oligosilylethers with ferrocene pendent to- (P1–P4) or as a constituent (P5, P6) of the main polymer chain were prepared from 1 or Fe(C 5H 4SiPhH 2) 2 (4) with diols 1,4-(HOCH 2) 2-(C 6H 4) and 1,4-(CH(CH 3)OH) 2-(C 6H 4), respectively. The resultant materials were characterized by NMR spectroscopy, gel permeation chromatography (GPC) and DOSY NMR spectroscopy, with estimated molecular weights in excess of 20,000 Da for P1 and P4. The iron centers display reversible redox behavior and thermal analysis showed P1 and P5 to be promising precursors to magnetic ceramic materials. </p

A Convenient Route to Monoalkyl-Substituted Phosphanylboranes (HRP–BH2–NMe3): Prospective Precursors to Poly[(alkylphosphino)boranes]

A simple method to access borylphosphonium iodides [RH2P-BH2 center dot NMe3]I (1a: R = Me; 1b: R = Et; 1c: R = nPr) by the addition of iodoalkanes to PH2-BH2 center dot NMe3 was developed. Complexes 1a-c were characterized by multinuclear NMR spectroscopy, and 1a and 1b additionally by single-crystal X-ray diffraction. It was possible to synthesize the Lewis-base-stabilized organosubstituted phosphanylborane MePH-BH2 center dot NMe3 (2) from [MePH2-BH2 center dot NMe3] I (1a). Thermolysis of 2 generated a soluble, low-molecular-mass poly(alkylphosphinoborane)consisting of at least 40 repeat units, as identified by ESI-MS. These results are promising for the future preparation of a wide range of Lewis-base-stabilized phosphanylboranes, which are of interest as precursors to poly[(alkylphosphino)boranes] and are otherwise difficult to access by conventional metal-catalyzed methods

Discovery of lead compounds targeting the bacterial sliding clamp using a fragment-based approach

The bacterial sliding clamp (SC), also known as the DNA polymerase III β subunit, is an emerging antibacterial target that plays a central role in DNA replication, serving as a protein-protein interaction hub with a common binding pocket to recognize linear motifs in the partner proteins. Here, fragment-based screening using X-ray crystallography produced four hits bound in the linear-motif-binding pocket of the Escherichia coli SC. Compounds structurally related to the hits were identified that inhibited the E. coli SC and SC-mediated DNA replication in vitro. A tetrahydrocarbazole derivative emerged as a promising lead whose methyl and ethyl ester prodrug forms showed minimum inhibitory concentrations in the range of 21-43 μg/mL against representative Gram-negative and Gram-positive bacteria species. The work demonstrates the utility of a fragment-based approach for identifying bacterial sliding clamp inhibitors as lead compounds with broad-spectrum antibacterial activity. © 2014 American Chemical Society

Ferrocene-Containing Polycarbosilazanes via the Alkaline-Earth-Catalyzed Dehydrocoupling of Silanes and Amines

We report the use of the alkaline-earth (Ae) metal-catalyzed dehydrocoupling of silanes and amines for the synthesis of ferrocene-containing polycarbosilazanes. The barium complex [Ba(N(SiMe 3) 2) 2·(THF) 2] catalyzed the dehydrocoupling of the hydrosilane FeCp(CpSiPhH 2) (1) with 1,4-(H 2NCH 2) 2C 6H 4 under mild conditions to give a polycarbosilazane with pendant ferrocene groups. The polymer could be readily cross-linked by the addition of phenylsilane to the unquenched reaction mixture. Well-defined polycarbosilazanes with ferrocene in the main chain were also obtained from the dehydrocoupling of hydrosilanes Fe(Cp(SiPhH 2)) 2 (3) and Fe(Cp(SiMe 2H)) 2 (IX) with 1,4-(H(Me)NCH 2) 2C 6H 4 and 1,4-(H 2NCH 2) 2C 6H 4, respectively. Crystalline monomeric analogues, FeCp(Cp(SiPh(NHBn) 2)) (2, Bn = CH 2(C 6H 5)), and Fe(Cp(SiPh(NHBn) 2)) 2 (4), were also obtained via the dehydrocoupling benzylamine with 1 and 3, respectively. The barium-catalyzed dehydrocoupling of diaminoferrocene with Ph 2SiH 2 or Ph(Rc)SiH 2 (6, Rc = (C 5H 4)Ru(C 5H 5)) did not result in polymer, but instead in the formation of the silazane-bridged ansa-[3]ferrocenophanes (Fe(ν-C 5H 4NH) 2SiPh 2) (5) and (Fe(ν-C 5H 4NH) 2SiPh(Rc)) (7), respectively. Both polymeric and molecular products were electrochemically investigated, and the polymers proved to be promising precursors to magnetic iron-containing ceramics in yields of up to 64%. </p