Shabana I. Khan

Chemistry of functionalized silylenes

Recent years have witnessed important developments in organosilicon chemistry, courtesy to the high yield access of stable monomeric chlorosilylene (LSiCl, L = PhC(NtBu)2) and N-heterocyclic carbene (NHC) stabilized dichlorosilylene (L1SiCl2, L1 = 1,3-bis(2,6-iPr2C6H3)imidazol-2-ylidene) by dehydrochlorination technique using strong bases such as N-heterocyclic carbenes or LiN(SiMe3)2 as HCl scavenger. The chemistry of functionalized silylenes is markedly different from the previously reported dicoordinate silylenes. Their utility as synthons is well documented which paves the way for several striking compounds, e.g. monosilaoxiranes, CSi2P derivative, CSi3P cation, a dimer of silaisonitrile (Si2N2) with dicoordinate Si atoms etc. This study also unravels that these functionalized silylenes are proficient at activating phosphorus, and the functional group attached to the α-position of the silicon(II) centre plays a key role to determine the final product. The reaction of P4 with LSiCl affords a zwitterionic Si2P2 ring, while with LSiN(SiMe3)2 it gives an acyclic Si2P4 derivative. Another recent achievement in this field is the successful isolation of a valence isomer of disilyne known as the inter-connected bis-silylene. This perspective portrays the chemistry of functionalized silylenes which will attract great attention, heading for the further development of organosilicon chemistry.

Epigenetic Events Associated with Breast Cancer and Their Prevention by Dietary Components Targeting the Epigenome

Aberrant epigenetic alterations in the genome such as DNA methylation and chromatin remodeling play a significant role in breast cancer development. Since epigenetic alterations are considered to be more easily reversible compared to genetic changes, epigenetic therapy is potentially very useful in reversing some of these defects. Methylation of CpG islands is an important component of the epigenetic code, and a number of genes become abnormally methylated in breast cancer patients. Currently, several epigenetic-based synthetic drugs that can reduce DNA hypermethylation and histone deacetylation are undergoing preclinical and clinical trials. However, these chemicals are generally very toxic and do not have gene specificity. Epidemiological studies have shown that Asian women are less prone to breast cancer due to their high consumption of soy food than the Caucasian women of western countries. Moreover, complementary/and or alternative medicines are commonly used by Asian populations which are rich in bioactive ingredients known to be chemopreventive against tumorigenesis in general. Examples of such agents include dietary polyphenols, (-)-epigallocatechin-3-gallate (EGCG) from green tea, genistein from soybean, isothiocyanates from plant foods, curcumin from turmeric, resveratrol from grapes, and sulforaphane from cruciferous vegetables. These bioactive components are able to modulate epigenetic events, and their epigenetic targets are known to be associated with breast cancer prevention and therapy. This approach could facilitate the discovery and development of novel drugs for the treatment of breast cancer. In this brief review, we will summarize the epigenetic events associated with breast cancer and the potential of some of these bioactive dietary components to modulate these events and thus afford new therapeutic or preventive approaches.

Novel 4-aminoquinoline-pyrimidine based hybrids with improved in vitro and in vivo antimalarial activity.

A class of hybrid molecules consisting of 4-aminoquinoline and pyrimidine were synthesized and tested for antimalarial activity against both chloroquine (CQ)-sensitive (D6) and chloroquine (CQ)-resistant (W2) strains of Plasmodium falciparum through an in vitro assay. Eleven hybrids showed better antimalarial activity against both CQ-sensitive and CQ-resistant strains of P. falciparum in comparison to standard drug CQ. Four molecules were more potent (7-8-fold) than CQ in D6 strain, and eight molecules were found to be 5-25-fold more active against resistant strain (W2). Several compounds did not show any cytotoxicity up to a high concentration (60 μM), others exhibited mild toxicities, but the selective index for the antimalarial activity was very high for most of these hybrids. Two compounds selected for in vivo evaluation have shown excellent activity (po) in a mouse model of Plasmodium berghei without any apparent toxicity. The X-ray crystal structure of one of the compounds was also determined.

Interconnected Bis-Silylenes: A New Dimension in Organosilicon Chemistry

The past two decades have brought remarkable advances in organosilicon chemistry with the isolation of stable silylenes, persila-allene, and disilynes. The extension of this list gives an impression that it will continue to flourish. The judicous employment of sterically appropriate ligands has enabled the synthesis and isolation of compounds with low-valent silicon. Recently, for example, interconnected bis-silylenes were isolated where the two Si atoms are connected by a σ-bond and each Si atom is possessing a lone pair of electrons. The formal oxidation state of each Si atom in the interconnected bis-silylene is +1, so bis-silylenes can be considered as the valence isomers of disilynes. In this Account, we describe the synthesis of interconnected bis-silylenes and assess their potential as a new building block in organosilicon chemistry. In 2009, we reported the isolation of a bis-silylene ((PhC(NtBu)(2))(2)Si(2)) stabilized by a sterically bulky benz-amidinato ligand with tBu substituents on the nitrogen atoms. Prior to our work, Robinson and co-workers described the synthesis of a N-heterocyclic carbene stabilized bis-silylene. In following years, just two more interconnected bis-silylenes have been reported. Density functional theory calculations to establish the geometric and electronic structures of the reported bis-silylenes have shown that the Wiberg bond index (WBI) for all the reported bis-silylenes is ~1. The synthesis of stable (PhC(NtBu)(2))(2)Si(2) prompted explorations of its reactivity. An important facet of silylene chemistry involves oxidative addition at the Si(II) center with unsaturated substrates, a reaction also available for bis-silylenes. Due to the three reaction sites (two lone pairs of electrons and a labile Si(I)-Si(I) single bond) in the interconnected bis-silylenes, we expect novel product formation. A labile Si-Si bond facilitates the reactions of (PhC(NtBu)(2))(2)Si(2) with diphenyl alkyne or adamantyl phosphaalkyne which afforded 1,4- disilabenzene and 1,3-disilacarbaphosphide (CSi(2)P) derivatives, respectively. The former is a noteworthy addition to the silicon analogues of benzene, and the latter serves as a heavy cyclobutadiene. With white phosphorus, a cyclic Si(2)P(2) derivative, an analogue of cyclobutadiene was obtained. The most predominant structural feature of these heavy cyclobutadienes is the presence of two-coordinate P atoms.

Preparation of RSn(I)–Sn(I)R with Two Unsymmetrically Coordinated Sn(I) Atoms and Subsequent Gentle Activation of P4

This article reports the reduction of [{2,6-iPr(2)C(6)H(3)NC(CH(3))}(2)C(6)H(3)SnCl] (1) with potassium graphite to afford a new distannyne [{2,6-iPr(2)C(6)H(3)NC(CH(3))}(2)C(6)H(3)Sn](2) (2) with a Sn-Sn bond. The most striking phenomenon of 2 is the presence of two differently coordinated Sn atoms (one is three-coordinated, the other is four-coordinated). The Sn-Sn bond length in 2 is 2.8981(9) Å, which is very close to that of a Sn-Sn single bond (2.97-3.06 Å). To elucidate the nature of the Sn-Sn bond, DFT calculation is carried out that shows there is no multiple bond character in 2. Furthermore, the reaction of 2 with white P(4) affords the tetraphosphabicylobutane derivative 3. This is the first example of gentle activation of white phosphorus by a compound with low valent Sn atoms. Note that, unlike 2, in 3 both Sn atoms are four-coordinated.

Biological Activity of Peanut (Arachis hypogaea) Phytoalexins and Selected Natural and Synthetic Stilbenoids

The peanut plant (Arachis hypogaea L.), when infected by a microbial pathogen, is capable of producing stilbene-derived compounds that are considered antifungal phytoalexins. In addition, the potential health benefits of other stilbenoids from peanuts, including resveratrol and pterostilbene, have been acknowledged by several investigators. Despite considerable progress in peanut research, relatively little is known about the biological activity of the stilbenoid phytoalexins. This study investigated the activities of some of these compounds in a broad spectrum of biological assays. Since peanut stilbenoids appear to play roles in plant defense mechanisms, they were evaluated for their effects on economically important plant pathogenic fungi of the genera Colletotrichum, Botrytis, Fusarium, and Phomopsis. We further investigated these peanut phytoalexins, together with some related natural and synthetic stilbenoids (a total of 24 compounds) in a panel of bioassays to determine their anti-inflammatory, cytotoxic, and antioxidant activities in mammalian cells. Several of these compounds were also evaluated as mammalian opioid receptor competitive antagonists. Assays for adult mosquito and larvae toxicity were also performed. The results of these studies reveal that peanut stilbenoids, as well as related natural and synthetic stilbene derivatives, display a diverse range of biological activities.

Synthesis of Stable Silicon Heterocycles by Reaction of Organic Substrates with a Chlorosilylene [PhC(NtBu)2SiCl]

Heteroleptic chlorosilylene (PhC(NtBu)(2)SiCl) (1) reacts with unsaturated organic compounds under oxidative addition. Reactions of 1 with cyclooctatetraene (COT) and a diimine afford [1+4]-cycloaddition products 3 and 6, respectively. In the case of COT, one Si-N bond of the amidinato ligand is cleaved, resulting in tetracoordinate silicon, whereas with a diimine a pentacoordinate silicon is formed. Treatment of 1 with ArN=C=NAr (Ar=2,6-iPr(2)C(6)H(3)) yields silaimine complex 4 with cleavage of one of the C=N bonds. The facile isolation of silaimine complexes is probably due to the kinetic protection afforded by the bulky Ar moiety. When 1 is treated with tert-butyl isocyanate, cleavage of the C=O bond is observed, which leads to formation of the four-membered Si(2)O(2) cycle 5. The same product is formed when 1 is allowed to react with trimethylamine N-oxide. When 1 is treated with diphenyl disulfide, cleavage of the S-S bond occurs to form 7. All products have been characterized by multinuclear NMR spectroscopy, EI mass spectrometry, and elemental analysis. In addition, the molecular structures of 3-6 have been determined by single-crystal X-ray diffraction studies. Collectively, these results suggest that owing to the presence of the lone pair of electrons, the propensity of 1 to undergo oxidative addition is very high.

Potent in vitro antifungal activities of naturally occurring acetylenic acids.

ABSTRACT Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C16 to C20: 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 μM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 μmol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.

Synthesis and Biological Evaluation of Some Hydrazone Derivatives as Anti-inflammatory Agents

In the present study, some hydrazone derivatives were synthesized via the reaction of 3-cyclohexylpropionic acid hydrazide with various benzaldehydes. The chemical structures of the compounds were elucidated by spectroscopic techniques such as IR, 1 H-NMR and FAB-MS and elemental analyses. The compounds were evaluated for their anti- inflammatory and cytotoxic activities. Anti-inflammatory activity was determined in terms of inhibition of NF-! B, ROS generation and iNOS activity. Several derivatives inhibited NF-! B and iNOS, but no effect was observed on intracellular ROS generation. Furthermore no cytoxicity was observed. Biological activity compared with the chemical structural information suggests that different functional groups on the phenyl ring influence the physicochemical properties and thus modulate biological activity.

Monomeric Sn(II) and Ge(II) hydrides supported by a tridentate pincer-based ligand

Herein we report the syntheses of terminal Sn(II) (3) and Ge(II) (4) hydrides from the corresponding chloride precursors [{2,6-iPr(2)C(6)H(3)NCMe}(2)C(6)H(3)MCl] (M = Sn (1), Ge (2)) using [K{B(sec-Bu)(3)}H] as a hydrogenating agent. Combination of steric shielding and intramolecular N → M interactions resulted in the protection of M(II)-H bonds.