Victor Wee Lin Ng

Synthesis of cis,syndiotactic ROMP Polymers Containing Alternating Enantiomers

Ring-opening metathesis polymerization (ROMP) of rac-endo,exo-5,6-dicarbomethoxynorbornene (inter alia) yields a cis,syndio,alt-polymer, one in which the sequential units in the cis,syndiotactic polymer consist of alternating enantiomers. Cis selectivity arises through addition of the monomer to produce an all-cis-metallacyclobutane intermediate, while syndioselectivity and alternating enantiomer structures arise as a consequence of inversion of configuration at the metal center with each metathesis step.

Antimicrobial hydrogels: A new weapon in the arsenal against multidrug-resistant infections☆

The rapid emergence of antibiotic resistance in pathogenic microbes is becoming an imminent global public health problem. Treatment with conventional antibiotics often leads to resistance development as the majority of these antibiotics act on intracellular targets, leaving the bacterial morphology intact. Thus, they are highly prone to develop resistance through mutation. Much effort has been made to develop macromolecular antimicrobial agents that are less susceptible to resistance as they function by microbial membrane disruption. Antimicrobial hydrogels constitute an important class of macromolecular antimicrobial agents, which have been shown to be effective in preventing and treating multidrug-resistant infections. Advances in synthetic chemistry have made it possible to tailor molecular structure and functionality to impart broad-spectrum antimicrobial activity as well as predictable mechanical and rheological properties. This has significantly broadened the scope of potential applications that range from medical device and implant coating, sterilization, wound dressing, to antimicrobial creams for the prevention and treatment of multidrug-resistant infections. In this review, advances in both chemically and physically cross-linked natural and synthetic hydrogels possessing intrinsic antimicrobial properties or loaded with antibiotics, antimicrobial polymers/peptides and metal nanoparticles are highlighted. Relationships between physicochemical properties and antimicrobial activity/selectivity, and possible antimicrobial mechanisms of the hydrogels are discussed. Approaches to mitigating toxicity of metal nanoparticles that are encapsulated in hydrogels are reviewed. In addition, challenges and future perspectives in the development of safe and effective antimicrobial hydrogel systems especially involving co-delivery of antimicrobial polymers/peptides and conventional antimicrobial agents for eventual clinical applications are presented.

Role of non-covalent and covalent interactions in cargo loading capacity and stability of polymeric micelles

Polymeric micelles self-assembled from biodegradable amphiphilic block copolymers have been proven to be effective drug delivery carriers that reduce the toxicity and enhance the therapeutic efficacy of free drugs. Several reviews have been reported in the literature to discuss the importance of size/size distribution, stability and drug loading capacity of polymeric micelles for successful in vivo drug delivery. This review is focused on non-covalent and covalent interactions that are employed to enhance cargo loading capacity and in vivo stability, and to achieve nanosize with narrow size distribution. In particular, this review analyzes various non-covalent and covalent interactions and chemistry applied to introduce these interactions to the micellar drug delivery systems, as well as the effects of these interactions on micelle stability, drug loading capacity and release kinetics. Moreover, the factors that influence these interactions and the future research directions of polymeric micelles are discussed.

A Simple and Facile Approach to Aliphatic N-Substituted Functional Eight-Membered Cyclic Carbonates and Their Organocatalytic Polymerization.

Aliphatic N-substituted functional eight-membered cyclic carbonates were synthesized from N-substituted diethanolamines by intramolecular cyclization. On the basis of the N-substituent, three major subclasses of carbonate monomers were synthesized (N-aryl, N-alkyl and N-carbamate). Organocatalytic ring opening polymerization (ROP) of eight-membered cyclic carbonates was explored as a route to access narrowly dispersed polymers of predictable molecular weights. Polymerization kinetics was highly dependent on the substituent on the nitrogen atom and the catalyst used for the reaction. The use of triazabicyclodecene (TBD), instead of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), as the catalyst for the N-alkyl substituted monomers significantly enhanced the rate of polymerizations. Computational studies were performed to rationalize the observed trends for TBD catalyzed polymerizations. With the optimal organocatalyst all monomers could be polymerized generating well-defined polymers within a timespan of ≤2 h with relatively high monomer conversion (≥80%) and low molar-mass dispersity (Đ(M) ≤ 1.3). Both the glass transition temperatures (T(g)) and onset of degradation temperatures (T(onset)) of these polymers were found to be N-substituent dependent and were in the range of about -45 to 35 °C and 230 to 333 °C, respectively. The copolymerization of the eight membered monomers with 6-membered cyclic comonomers including commercially available l-lactide and trimethylene carbonate produced novel copolymers. The combination of inexpensive starting materials, ease of ring-closure and subsequent polymerization makes this an attractive route to functional polycarbontes.

Injectable Biodegradable Hydrogels from Vitamin D-Functionalized Polycarbonates for the Delivery of Avastin with Enhanced Therapeutic Efficiency against Metastatic Colorectal Cancer

Humanized vascular endothelial growth factor (VEGF) antibody (bevacizumab; Avastin) is a highly effective monoclonal antibody against metastatic colorectal cancer and several other advanced late stage cancers. However, limited aqueous solubility and short circulation half-life of the antibody result in long infusion time (30-90 min) and frequent injections. Such direful medical procedures often cause considerable patient inconvenience and prolonged pharmacy preparation. Subcutaneous delivery of Avastin using injectable hydrogels can continuously provide Avastin to treat the malignancy and mitigate antibody degradation. In this study, ABA triblock copolymers of vitamin D-functionalized polycarbonate and poly(ethylene glycol), that is, VDm-PEG-VDm were synthesized and employed to form physically cross-linked injectable hydrogels for encapsulation and subcutaneous delivery of Avastin in a sustained fashion. Antitumor studies were performed using two different HCT116 xenograft mouse models: a subcutaneous and an intraperitoneal metastatic tumor models. The therapeutic efficacy of Avastin-loaded hydrogel injected subcutaneously (s.c.) was compared to an Avastin solution injected via either intravenous (i.v.) or intraperitoneal (i.p.) route. In the subcutaneous tumor model, the Avastin-loaded hydrogel resulted in greater tumor suppression as compared to i.v. and i.p. administration of Avastin solution. The biodistribution pattern of the hydrogel delivery system was also different from the other formulations as there was significantly higher accumulation in the tumor tissue and lesser accumulation within the liver and kidneys as compared to Avastin delivered through i.v. and i.p. administration. Furthermore, in vivo studies carried out on mice with peritoneal metastasis demonstrated that Avastin-loaded hydrogel and weekly administration of Avastin solution resulted in higher survival (87 and 77% over 62 days, respectively) when compared to the control, blank hydrogel and bolus Avastin solution (i.v.; 50-60%). The antimetastatic activity of Avastin delivered using a one-time injection of the hydrogel was as effective as that of 4× weekly injections (i.v.) of Avastin. The reduced injection frequency provided by the subcutaneous formulation may enhance patient convenience and compliance for metastatic cancer therapy.

Toward Multifunctional Mo(VI-IV) Complexes: cis-Dioxomolybdenum(VI) Complexes Containing Hydrogen-Bond Acceptors or Donors

The complexes cis-TpiPrMoVIO2(OAr-R) (TpiPr=hydrotris(3-isopropylpyrazol-1-yl)borate, -OAr-R=hydrogen-bonding phenolate derivative) are formed upon reaction of TpiPrMoO2Cl, HOAr-R, and NEt3 in dichloromethane. The orange, diamagnetic, dioxo-Mo(VI) complexes exhibit strong nu(MoO2) IR bands at ca. 935 and 900 cm(-1) and NMR spectra indicative of Cs symmetry. They undergo electrochemically reversible, one-electron reductions at potentials in the range -0.836 to -0.598 V vs SCE; the only exception is the 2-CO2Ph derivative, which exhibits an irreversible reduction at -0.924 V. The complexes display distorted octahedral geometries, with a cis arrangement of terminal oxo ligands and with d(Mo=O)av=1.695 A and angle(MoO2)av=103.2 degrees. The R groups of the 2-CHO and 2-NHCOMe derivatives are directed away from the oxo groups and into a cleft in the TpiPr ligand; these derivatives are characterized by Mo-O-Cipso angles of ca. 131 degrees (conformation 1). The R group(s) in the 2-CO2Me and 2,3-(OMe)2 derivatives lie above the face of the three O-donor atoms (directed away from the TpiPr ligand) and the complexes display Mo-O-Cipso angles of 153.1(2) and 149.7(2) degrees, respectively (conformation 2). Conformations 1 and 2 are both observed in the positionally disordered 2-COMe and 2-COEt derivatives, the two conformers having Mo-O-Cipso angles of 130-140 and >150 degrees, respectively. The 3-COMe and 3-NEt2 derivatives have substituents that project away from the TpiPr ligand and Mo-O-Cipso angles of 134.2(2) and 147.7(2) degrees, respectively. Many of the complexes exhibit fluxional behavior on the NMR time scale, consistent with the rapid interconversion of two conformers in solution.

Amphiphilic and Hydrophilic Block Copolymers from Aliphatic N-Substituted 8-Membered Cyclic Carbonates: A Versatile Macromolecular Platform for Biomedical Applications.

Introduction of hydrophilic components, particularly amines and zwitterions, onto a degradable polymer platform, while maintaining precise control over the polymer composition, has been a challenge. Recognizing the importance of these hydrophilic residues in multiple aspects of the nanobiomedicine field, herein, a straightforward synthetic route to access well-defined amphiphilic and hydrophilic degradable block copolymers from diethanolamine-derived functional eight-membered N-substituted aliphatic cyclic carbonates is reported. By this route, tertiary amine, secondary amine, and zwitterion residues can be incorporated across the polymer backbone. Demonstration of pH-responsiveness of these hydrophilic residues and their utility in the development of drug-delivery vehicles, catered for the specific requirements of respective model drugs (doxorubicin and diclofenac sodium salt) are shown. As hydrophilic components in degradable polymers play crucial roles in the biological interactions, these materials offers opportunities to expand the scope and applicability of aliphatic cyclic carbonates. Our approach to these functional polycarbonates will expand the range of biocompatible and biodegradable synthetic materials available for nanobiomedicine, including drug and gene delivery, antimicrobials, and hydrophilic polymers as poly(ethylene glycol) (PEG) alternatives.

cis-Dioxo- and cis-(hydroxo)oxo-Mo(V) complexes stabilized by intramolecular hydrogen-bonding.

The reactions of Tp(iPr)Mo(VI)O(2)Cl with salicylanilides and NEt(3) produce cis-Tp(iPr)Mo(VI)O(2)(2-OC(6)H(4)CONHR) (Tp(iPr) = hydrotris(3-isopropylpyrazol-1-yl)borate, R = Ph, 4-C(6)H(4)Cl, 4-C(6)H(4)OMe). The N-methyl complex, Tp(iPr)MoO(2){2-OC(6)H(4)CON(Me)Ph}, is similarly prepared. Reduction of the amido complexes by cobaltocene produces green, EPR-active compounds, [CoCp(2)][Tp(iPr)Mo(V)O(2)(2-OC(6)H(4)CONHR)], that exhibit strong, low energy, ν(MoO(2)) IR bands at ∼ 895 and 790 cm(-1) (cf. ∼ 935 and 900 cm(-1) for the Mo(VI) analogues). The X-ray structures of all seven complexes have been determined. In each case, the Mo center exhibits a distorted octahedral coordination geometry defined by mutually cis oxo and phenolate ligands and a tridentate fac-Tp(iPr) ligand. The Mo(V) anions exhibit greater Mo═O distances (av. 1.738 Å vs 1.695 Å) and O═Mo═O angles (av. 112.4° vs 102.9°) than their Mo(VI) counterparts, indicative of the presence of a three-center (MoO(2)), π* semioccupied molecular orbital in these d(1) complexes. The amido Mo(VI) and Mo(V) complexes exhibit an intramolecular hydrogen-bond between the NH and O(phenolate) atoms. Protonation of [CoCp(2)][Tp(iPr)Mo(V)O(2)(2-OC(6)H(4)CONHR)] by lutidinium tetrafluoroborate is quantitative and produces EPR-active, cis-(hydroxo)oxo-Mo(V) complexes, Tp(iPr)Mo(V)O(OH)(2-OC(6)H(4)CONHR), related to the low pH Mo(V) forms of sulfite oxidase.

Co-delivery of antiviral and antifungal therapeutics for the treatment of sexually transmitted infections using a moldable, supramolecular hydrogel.

In this investigation, a therapeutic co-delivery hydrogel system is developed to provide effective HIV prophylaxis, alongside the prevention and/or treatment of candidiasis. Two components-a HIV reverse transcriptase inhibitor, tenofovir, and a cationic macromolecular antifungal agent derived from a vitamin D-functionalized polycarbonate (VD/BnCl (1:30))-are formulated into biodegradable vitamin D-functionalized polycarbonate/PEG-based supramolecular hydrogels. The hydrogels exhibit thixotropic properties and can be easily spread across surfaces for efficient drug absorption. Sustained release of tenofovir from the hydrogel is observed, where approximately 85% tenofovir is released within 3 h. VD/BnCl (1:30) does not impede drug diffusion from the hydrogel as the drug release profiles are similar with and without the polycation. Antimicrobial efficacy studies indicate that the hydrogels kill C. albicans efficiently with a minimum bactericidal concentration (MBC) of 0.25-0.5 g L(-1) . These hydrogels also eradicate C. albicans biofilm effectively at 4× MBC. When human dermal fibroblasts (as model mammalian cells) are treated with these hydrogels, cell viability remains high at above 80%, demonstrating excellent biocompatibility. When applied topically, this dual-functional hydrogel can potentially prevent HIV transmission and eliminate microbes that cause infections in the vulvovagina region.

d1 Oxosulfido-Mo(V) Compounds: First Isolation and Unambiguous Characterization of an Extended Series

Reaction of Tp(iPr)Mo(VI)OS(OAr) with cobaltocene in toluene results in the precipitation of brown, microcrystalline oxosulfido-Mo(V) compounds, [CoCp2][Tp(iPr)Mo(V)OS(OAr)] (Cp(-) = η(5)-C5H5(-), Tp(iPr)(-) = hydrotris(3-isopropylpyrazol-1-yl)borate, OAr(-) = phenolate or 2-(s)Bu, 2-(t)Bu, 3-(t)Bu, 4-(s)Bu, 4-Ph, 3,5-(s)Bu2, 2-CO2Me, 2-CO2Et or 2-CO2Ph derivative thereof). The compounds are air- and water-sensitive and display ν(Mo═O) and ν(Mo[Formula: see text]S) IR absorption bands at ca. 890 and 435 cm(-1), respectively, 20-40 cm(-1) lower in energy than the corresponding bands in Tp(iPr)MoOS(OAr). They are electrochemically active and exhibit three reversible cyclovoltammetric waves (E(Mo(VI)/Mo(V)) = -0.40 to -0.66 V, E([CoCp2](+)/CoCp2) = -0.94 V and E(CoCp2/[CoCp2](-)) = -1.88 V vs SCE). Structural characterization of [CoCp2][Tp(iPr)MoOS(OC6H4CO2Et-2)]·2CH2Cl2 revealed a distorted octahedral Mo(V) anion with Mo═O and Mo[Formula: see text]S distances of 1.761(5) and 2.215(2) Å, respectively, longer than corresponding distances in related Tp(iPr)MoOS(OAr) compounds. The observation of strong S(1s) → (S(3p) + Mo(4d)) S K-preedge transitions indicative of a d(1) sulfido-Mo(V) moiety and the presence of short Mo═O (ca. 1.72 Å) and Mo[Formula: see text]S (ca. 2.25 Å) backscattering contributions in the Mo K-edge EXAFS further support the oxosulfido-Mo(V) formulation. The compounds are EPR-active, exhibiting highly anisotropic (Δg 0.124-0.150), rhombic, frozen-glass spectra with g1 close to the value observed for the free electron (ge = 2.0023). Spectroscopic studies are consistent with the presence of a highly covalent Mo[Formula: see text]S π* singly occupied molecular orbital. The compounds are highly reactive, with reactions localized at the terminal sulfido ligand. For example, the compounds react with cyanide and PPh3 to produce thiocyanate and SPPh3, respectively, and various (depending on solvent) oxo-Mo(V) species. Reactions with copper reagents also generally lead to desulfurization and the formation of oxo-Mo(V) or -Mo(IV) complexes.