Tariq R. Sobahi

Tumor Targeting via Integrin Ligands

Selective and targeted delivery of drugs to tumors is a major challenge for an effective cancer therapy and also to overcome the side-effects associated with current treatments. Overexpression of various receptors on tumor cells is a characteristic structural and biochemical aspect of tumors and distinguishes them from physiologically normal cells. This abnormal feature is therefore suitable for selectively directing anticancer molecules to tumors by using ligands that can preferentially recognize such receptors. Several subtypes of integrin receptors that are crucial for cell adhesion, cell signaling, cell viability, and motility have been shown to have an upregulated expression on cancer cells. Thus, ligands that recognize specific integrin subtypes represent excellent candidates to be conjugated to drugs or drug carrier systems and be targeted to tumors. In this regard, integrins recognizing the RGD cell adhesive sequence have been extensively targeted for tumor-specific drug delivery. Here we review key recent examples on the presentation of RGD-based integrin ligands by means of distinct drug-delivery systems, and discuss the prospects of such therapies to specifically target tumor cells.

Integrin modulators: a patent review

Introduction: Integrins are heterodimeric cell surface receptors, which enable adhesion, proliferation, and migration of cells by recognizing binding motifs in extracellular matrix (ECM) proteins. As transmembrane linkers between the cytoskeleton and the ECM, they are able to recruit a huge variety of proteins and to influence signaling pathways bidirectionally, thereby regulating gene expression and cell survival. Hence, integrins play a key role in various physiological as well as pathological processes, which has turned them into an attractive target for pharmaceutical research. Areas covered: In this review, the latest therapeutic developments of drug candidates and recently patented integrin ligands are summarized. Expert opinion: Integrins have been proven to be valuable therapeutic targets in the treatment of several inflammatory and autoimmune diseases, where leukocyte adhesion processes are regulated by them. Furthermore, they play an important role in pathological angiogenesis and tumor metastasis, being a promising target for cancer therapy.

Hydrogel Micropillars with Integrin Selective Peptidomimetic Functionalized Nanopatterned Tops: A New Tool for the Measurement of Cell Traction Forces Transmitted through αvβ3‐ or α5β1‐Integrins

Poly(ethylene glycol) micropillars with gold nanopatterns on top are functionalized with two integrin selective ligands. This platform is a powerful new tool to determine the specific contribution of traction forces involved in cell adhesion mediated by α5β1- and αvβ3-integrins. Cells adherent via α5β1-integrins have a tendency to exert higher maximum forces than cells adhering via αvβ3-integrins.

A Molecular Toolkit for the Functionalization of Titanium‐Based Biomaterials That Selectively Control Integrin‐Mediated Cell Adhesion

We present a click chemistry-based molecular toolkit for the biofunctionalization of materials to selectively control integrin-mediated cell adhesion. To this end, α5β1-selective RGD peptidomimetics were covalently immobilized on Ti-based materials, and the capacity to promote the selective binding of α5β1 was evaluated using a solid-phase integrin binding assay. This functionalization strategy yielded surfaces with a nine-fold increased affinity for α5β1, in comparison to control samples, and total selectivity against the binding of the closely related integrin αvβ3. Moreover, our methodology allowed the screening of several phosphonic acid containing anchoring units to find the best spacer-anchor moiety required for establishing an efficient binding to titanium and to promote selective integrin binding. The integrin subtype specificity of these biofunctionalized surfaces was further examined in vitro by inducing selective adhesion of genetically modified fibroblasts, which express exclusively the α5β1 integrin. The versatility of our molecular toolkit was proven by shifting the cellular specificity of the materials from α5β1- to αvβ3-expressing fibroblasts by using an αvβ3-selective peptidomimetic as coating molecule. The results shown here represent the first functionalization of Ti-based materials with α5β1- or αvβ3-selective peptidomimetics that allow an unprecedented control to discriminate between α5β1- and αvβ3-mediated adhesions. The role of these two integrins in different biological events is still a matter of debate and is frequently discussed in literature. Thus, such bioactive titanium surfaces will be of great relevance for the study of integrin-mediated cell adhesion and the development of new biomaterials targeting specific cell types.

Pharmacophoric Modifications Lead to Superpotent αvβ3 Integrin Ligands with Suppressed α5β1 Activity

The selective targeting of the αvβ3 integrin subtype without affecting the structurally closely related receptor α5β1 is crucial for understanding the details of their biological and pathological functions and thus of great relevance for diagnostic and therapeutic approaches in cancer treatment. Here, we present the synthesis of highly active RGD peptidomimetics for the αvβ3 integrin with remarkable selectivity against α5β1. Incorporation of a methoxypyridine building block into a ligand scaffold and variation of different functional moieties led to αvβ3-antagonistic activities in the low nanomolar or even subnanomolar range. Furthermore, docking studies were performed to give insights into the binding modes of the novel compounds. The presented library comprises powerful ligands for specific addressing and blocking of the αvβ3 integrin subtype, thereby representing privileged tools for integrin-based personalized medicine.

Chemical Degradation of Poly(Ethylene Terephthalate)

The possibility of converting polyethylene terephthalate (PET) waste into terephthalic acid as a primary material by using different techniques through trans-esterification, with an alcohol and through hydrolysis in basic medium, has been investigated. In addition, utilization of activating agents such as inorganic salts and phase transfer catalysts has been investigated.Mineral water and beverage bottles were collected, cleaned and crushed into flakes suitable for the intended experiments. Also, the main products of chemical conversion of such wastes were isolated and confirmed by authentication with standard terephthalic acid through Thin Layer Chromatography (TLC) technique. The reaction yield % was determined to optimize the corresponding experimental conditions and the obtained results have been presented and discussed.

Development of Hg2+ sensor based on N′-[1-(pyridin-2-yl)ethylidene]benzenesulfono-hydrazide (PEBSH) fabricated silver electrode for environmental remediation

N′-[1-(Pyridin-2-yl)ethylidene]benzenesulfonohydrazide (PEBSH) was synthesized via a simple condensation of 2-acetyl pyridine and benzene sulfonyl hydrazide in very good yield and crystallized in methanol. The characterization of title compound were accomplished using highly sophisticated spectroscopic techniques like, UV/VIS, IR, 1H-NMR and 13C-NMR. Finally the structure was determined with single crystal X-ray diffraction techniques for its further usage in detection of cations. Then a thin-layer of PEBSH onto flat-silver electrode (AgE) is deposited with conducting coating agents to fabricate a sensitive and selective Hg2+ ions sensor in short response time in phosphate buffer phase. The fabricated cationic-sensor is also exhibited higher sensitivity, large-dynamic concentration ranges, long-term stability, and improved electrochemical performances towards mercury ions. The calibration plot is linear (r2 = 0.9799) over the large Hg2+ concentration ranges (0.1 nM to 1.0 mM). The sensitivity and detection limit is ∼2.1897 μA mM cm−2 and ∼0.063 nM (signal-to-noise ratio, at a SNR of 3) respectively. This novel effort is initiated a well-organize way of efficient cationic sensor development with conducting binder deposited flat-electrode for toxic pollutants in environmental and health-care fields in large scales.

Carbon-supported PtCo 2 Ni 2 alloy with enhanced activity and stability for oxygen reduction

The commercialization of proton exchange membrane fuel cells (PEMFCs) is still restricted by the well-known dilemma, that is, the heavy dependence of using expensive plantinum (Pt) catalyst to negotiate the sluggish oxygen reduction reaction (ORR) kinetics in fuel cell cathodes. Here, a carbon-supported PtCo2Ni2 alloy catalyst with low Pt usage was synthesized via a simple method, which exhibited exceptional ORR activity with a more positive half-wave potential (E1/2) ∼57 mV, which was more positive than the state-of-the-art Pt/C catalysts. Moreover, the alloy catalyst performs excellent durability after 10,000 harsh cycles compared with that of Pt/C catalyst in acidic solution, which may be developed as a promising alternative for Ptbased catalysts in fuel cell technology.摘要近年来, 质子交换膜燃料电池由于高成本严重阻碍了其商业化进程, 而目前催化阴极氧气还原反应最高效的催化剂仍然是昂贵的铂催化剂, 因此设计、 开发制备少铂、 高效、 稳定的催化剂是目前此领域研究的热点. 本论文利用一种简便的制备方法得到了碳负载的铂钴镍(摩尔比=1:2:2)三元合金纳米颗粒催化剂, 这种合金化催化剂在改变铂电子结构的同时, 大大降低了贵金属铂的用量. 电化学测试结果显示这种多元合金催化剂的半波电势与商业铂碳相比提高了约57 mV, 而且优于同体系制备的二元合金催化剂和其他组分三元合金催化剂. 此外, 在酸性电解质溶液中, 此催化剂表现出更优异的稳定性. 在燃料电池技术领域, 这种多元合金化催化剂很可能在将来发展成新电催化剂来替代铂材料.

Modification of chitosan derivatives of environmental and biological interest: A green chemistry approach

Chitosan is a non-toxic polyaminosaccharide that is available in a variety of useful forms, and its chemical and biological properties make it a very attractive biomaterial that could be used in a wide variety of medicinal applications. This work focuses on the preparation of different chitosan derivatives by treatment with ethyl cellulose, cellulose triacetate and different carbohydrates in both neutral and slightly acidic media. It also addresses modification with glycidyltrimethyl ammonium chloride, phthalic anhydride and succinic acid derivatives. The obtained derivatives were crosslinked with glutaraldehyde. Thermo-gravimetric (TGA) and FT-IR spectroscopic analyses and electron scanning microscopy (SEM) were used to characterize the obtained products and demonstrate the success of the chitosan-modification process. The obtained products were tested for their ability to uptake transition metal ions from aqueous solutions, and their ion-uptake efficiency was determined with the aid of the ICP-AES technique. The bioactivity of some selected products was tested to study the effect of their concentrations on selected microorganisms. Burkholderia cepaci, Aspergillus niger, and Candida albicans were selected as representative examples of bacteria, yeasts and fungi, respectively.

An Efficient Approach to the Synthesis of Highly Congested 9,10-Dihydrophenanthrene-2,4-dicarbonitriles and Their Biological Evaluation as Antimicrobial Agents

An efficient and novel method for the synthesis in moderate to good yield (72%–84%) of a series of 3-amino-1-substituted-9,10-dihydrophenanthrene-2,4-dicarbonitriles 1–5 via one-pot multi-component reactions of aldehydes, malononitrile, 1-tetralone and ammonium acetate has been delineated. Cyclocondensation attempts of aminocyanophenanthrene derivatives 1, 2, 4 and 5 with acetic anhydride in the presence of conc. H2SO4 failed and instead the diacetylamino derivatives 10–13 were obtained. All prepared compounds were structurally elucidated by various spectroscopic methods and X-ray crystallography. N,N-diacetylamino-derivatives of phenanthrene have shown good antimicrobial activity.