Effects of N-terminus modified Hx-amides on DNA binding affinity, sequence specificity, cellular uptake, and gene expression.

Five X-HxIP (Hx-amides) 6a-e, in which the N-terminus p-anisyl moiety is modified, were designed and synthesised with the purpose of optimising DNA binding, improving cellular uptake/nuclear penetration, and enhancing the modulation of the topoisomerase IIα (TOP2A) gene expression. The modifications include a fluorophenyl group and other heterocycles bearing different molecular shapes, size, and polarity. Like their parent compound HxIP 3, all five X-HxIP analogues bind preferentially to their cognate sequence 5'-TACGAT-3', which is found embedded on the 5' flank of the inverted CCAAT box-2 (ICB2) site in the TOP2A gene promoter, and inhibit protein complex binding.

Alternate pathway for the click reaction of 2-(2-azidophenyl)-4,5-diaryloxazoles.

The CuSO/ascorbate-mediated 'click' reaction of 2-(2-azidophenyl)-4,5-diaryloxazoles and arylacetylenes proceeded through an alternate pathway whereby reduction of the azide predominated over formation of the 1,2,3-triazole-forming cycloaddition. The unimolecular product, 2-(2-aminophenyl)-4,5-diphenyloxazole, was isolated which appears to be a formal reduction of the arylazide to the corresponding arylamine. A series of oxazoles which possessed various substituents (F, Cl, Br, OCH) on the 4,5-diaryl rings and having the 2-azido group on the 2-oxazolylphenyl position were submitted to the same 'click' conditions and gave the corresponding arylamine products (73-99%).

'Second-generation' 1,2,3-triazole-based inhibitors of adherence to oral streptococci and biofilm formation.

Several 'second-generation' click inhibitors of the multi-species biofilm propagated by the adherence of the oral pathogen to were synthesized and evaluated. The design of the structures was based on the results obtained with the first-generation diphenyloxazole 'click' inhibitors which bear suitable hydrophobic and polar groups within a dual scaffold molecule bearing a 1,2,3-triazole spacer. The structures of the synthetic targets reported herein now consist of a triazolyl(phenylsulfonylmethyl) and a triazolyl(phenylsulfinylmethyl) spacer which joins a 4,5-diphenyloxazole with both phenyl rings bearing lipophilic substituents.

DNA-Binding Properties of New Fluorescent AzaHx Amides: Methoxypyridylazabenzimidazolepyrroleimidazole/pyrrole.

DNA minor groove binding polyamides have been extensively developed to control abnormal gene expression. The establishment of novel, inherently fluorescent 2-(p-anisyl)benzimidazole (Hx) amides has provided an alternative path for studying DNA binding in cells by direct observation of cell localization. Because of the 2:1 antiparallel stacking homodimer binding mode of these molecules to DNA, modification of Hx amides to 2-(p-anisyl)-4-azabenzimidazole (AzaHx) amides has successfully extended the DNA-recognition repertoire from central CG [recognized by Hx-I (I=N-methylimidazole)] to central GC [recognized by AzaHx-P (P=N-methylpyrrole)] recognition.

Unnatural Amino Acid Derivatives through Click Chemistry: Synthesis of Triazolylalanine Analogues.

A novel -butyl 2-(1-oxoisolndolin-2-yl)acetate derivative is selectively alkylated with propargyl bromide in the presence of lithium hexamethyldisilazide. After removal of the -butyl protecting group, the resulting -isoindolinyl (ethynylalanine) derivative is reacted with a series of azides under 'click conditions'. The click reactions afford an array of -isoindolinyl-1,2,3-triazolylalanine derivatives as the free carboxylic adds.

and Activity of Peptidomimetic Compounds That Target the Periodontal Pathogen Porphyromonas gingivalis.

The interaction of the periodontal pathogen with oral streptococci is important for initial colonization of the oral cavity by and is mediated by a discrete motif of the streptococcal antigen I/II protein. A synthetic peptide encompassing this motif functions as a potent inhibitor of adherence, but the use of peptides as topically applied therapeutic agents in the oral cavity has limitations arising from the relatively high cost of peptide synthesis and their susceptibility to degradation by proteases expressed by oral organisms. In this study, we demonstrate the and activity of five small-molecule mimetic compounds of the streptococcal peptide.

Design, synthesis, nuclear localization, and biological activity of a fluorescent duocarmycin analog, HxTfA.

HxTfA 4 is a fluorescent analog of a potent cytotoxic and antimalarial agent, TfA 3, which is currently being investigated for the development of an antimalarial vaccine, PlasProtect®. HxTfA contains a p-anisylbenzimidazole or Hx moiety, which is endowed with a blue emission upon excitation at 318 nm; thus enabling it to be used as a surrogate for probing the cellular fate of TfA using confocal microscopy, and addressing the question of nuclear localization. HxTfA exhibits similar selectivity to TfA for A-tract sequences of DNA, alkylating adenine-N3, albeit at 10-fold higher concentrations.

Selective alkylation/oxidation of -substituted isoindolinone derivatives: synthesis of -phthaloylated natural and unnatural α-amino acid analogues.

The interchangeability of the isoindolinone group as a nitrogen protecting group for amino acid intermediates is demonstrated by the preparation of several natural and unnatural α-amino acid derivatives using a two-carbon -isoindolinone (phthalimidine) scaffold. Using a selective benzylic oxidation, the -isoindolinone group is then converted to the -phthaloyl group for convenient removal (65-98%). For preparation of the isoindolinone products which were to be the substrates for benzylic oxidation, a range of side chains were installed on the isoindolinone-protected glycine equivalent on deprotonation to demonstrate the utility of the -protected isoindolinone synthon (51-93%).

-Chloroperbenzoic acid-oxchromium (VI)-mediated cleavage of 2,4,5-trisubstituted oxazoles.

An array of 2-substituted-4,5-diphenyloxazoles were found to be cleaved to triacylamines and diacylamines (imides) using a reagent system composed of 3-chloroperbenzoic acid (MCPBA) and 2,2'-bipyridinium chlorochromate (BPCC). The 2-alkyl-4,5-diphenyloxazoles give imides (38-60%) as the predominant cleavage product while the 2-aryl-4,5-diphenyloxazoles give triacylamines (44-71%). Two mechanisms involving intermediates such as cyclic endoperoxides or oxachromacycles were proposed.

The intramolecular click reaction using 'carbocontiguous' precursors.

The synthesis and utilization of all carbon-chain 'carbocontiguous' azidoalkynyl precursors for an intramolecular click reaction is described. The substrates contain both azidoalkyl and ethynylmethyl groups which are conjoined by a 2-(phenylsulfonylmethyl)-4,5-diphenyloxazole lynchpin and are suitably disposed for ring closure. On promotion by copper salts, a number of cyclic click products having the 1,4-disubstituted -fused triazole component and the 4,5-diphenyloxazole component are obtained.

Synthesis of Extended Oxazoles III: Reactions of 2-(Phenylsulfonyl)methyl-4,5-diaryloxazoles.

2-((Phenylsulfonyl)methyl)-4,5-diphenyloxazole is a useful scaffold for synthetic elaboration at the 2-methylene position thereby affording extended oxazoles. The corresponding α-sulfonyl anion reacts smoothly with diverse alkyl halides giving monoalkylated (47-90%), dialkylated (50-97%), and cyclic (59-93%) products. The reductive desulfonylation of the monoalkylated and selected dialkylated products was optimized with a magnesium/mercuric chloride reagent system and afforded desulfonylated products in the range of 66-97%.

1,2,3-Triazole-based inhibitors of Porphyromonas gingivalis adherence to oral streptococci and biofilm formation.

The development and use of small-molecule inhibitors of the adherence of Porphyromonas gingivalis to oral streptococci represents a potential therapy for the treatment of periodontal disease as these organisms work in tandem to colonize the oral cavity. Earlier work from these laboratories demonstrated that a small synthetic peptide was an effective inhibitor of the interaction between P. gingivalis and Streptococcus gordonii and that a small-molecule peptidomimetic would provide a more stable, less expensive and more effective inhibitor.

Synthesis of extended oxazoles II: Reaction manifold of 2-(halomethyl)-4,5-diaryloxazoles.

2-(Halomethyl)-4,5-diphenyloxazoles are effective, reactive scaffolds which can be utilized for synthetic elaboration at the 2-position. Through substitution reactions, the chloromethyl analogue is used to prepare a number of 2-alkylamino-, 2-alkylthio- and 2-alkoxy-(methyl) oxazoles. The 2-bromomethyl analogue offers a more reactive alternative to the chloromethyl compounds and is useful in the C-alkylation of a stabilized (malonate) carbanion as exemplified by a concise synthesis of Oxaprozin.

Oxazoles for click chemistry II: synthesis of extended heterocyclic scaffolds.

New routes to 2, 4, 5-trisubstituted oxazoles were established whereby the substitution pattern was established by the structure of the starting nonsymmetrical acyloins. 2-Chloromethyl-4, 5-disubstituted oxazoles were prepared by refinements of an earlier described process whereby chloroacetyl esters of symmetrical and non-symmetrical acyloins were cyclized using an ammonium acetate/acetic acid protocol. After substitution is effected, the azide moiety is then installed by substitution under mild conditions.

Recent advancement in discovery and development of natural product combretastatin-inspired anticancer agents.

The natural stilbenoids combretastatin A-4 (CA4) and combretastatin A-1 (CA1) are potent antitubulin agents demonstrating antimitotic activity as well as tumor vascular disruption property. Due to structural simplicity and potent cytotoxicity of CA4 and CA1, they are considered as promising leads for the development of potent anticancer agents. In fact, scientific fraternity is motivated to synthesize several derivatives of CA4 and CA1 as novel therapeutic agents.

A Short Review on the Synthetic Strategies of Duocarmycin Analogs that are Powerful DNA Alkylating Agents.

The duocarmycins and CC-1065 are members of a class of DNA minor groove, AT-sequence selective, and adenine-N3 alkylating agents, isolated from Streptomyces sp. that exhibit extremely potent cytotoxicity against the growth of cancer cells grown in culture. Initial synthesis and structural modification of the cyclopropa[c] pyrrolo[3,2-e]indole (CPI) DNA-alkylating motif as well as the indole non-covalent binding region in the 1980s have led to several compounds that entered clinical trials as potential anticancer drugs.