Development and novel applications of halogenating agents.

Organic halides are extensively utilized as synthetic intermediates in areas such as pharmaceuticals, agrochemicals, and material polymers. While many halogenating agents have been developed, they continue to have low efficiency or selectivity, are difficult to handle, and often have limited substrate scope. To address this issue, our laboratory has developed novel halogenating agents with improved stability and efficiency. In these studies, we demonstrated a novel application of halogenating reagent, HCl·DMPU, in the nitrile synthesis. We developed a novel method for C−SCF3/SeCF3 cross-coupling reactions using gold redox catalysis. We developed a novel trifluoromethylating agent in a cost-effective and highly efficient manner. We also attempted the development of dithiadication based electrophilic trifluoromethylating agents. With the objective of exploring other applications of HCl·DMPU beyond chlorination, we found a novel application of HCl·DMPU in one-pot conversion of aldehydes to nitriles. This method exhibited broad substrate scope with high yields for the aromatic, aliphatic, and α,β-unsaturated aldehydes incorporating various functional groups. We developed a novel application of halogenating agents like AgSCF3 and [(NMe4)(SeCF3)] in combination with commercially available gold catalyst [(MeDalphos)AuCl] for trifluoromethylthiolation (-SCF3) and trifluoromethylselenolation (-SeCF3) of the diverse array of aromatic, alkenyl and alkynyl halides and obtained the corresponding trifluoromethylthio and trifluoromethylseleno derivatives in good to excellent yields under mild reaction conditions . This protocol was successfully utilized in late-stage modification of various drug derivatives. In our quest of developing novel halogenating agents, we invented a newer version of Umemoto reagent II in one-pot synthesis from inexpensive starting material. This reagent is more powerful than Umemoto reagent II. and its applicability in the trifluoromethylation of various nucleophiles was demonstrated. In an attempt to explore the uncharted territory of trifluoromethylation, we designed and attempted to synthesize dithiadication electrophilic trifluoromethylating agents endowed with two transferable trifluoromethyl groups. However, our efforts to date have not produced satisfactory results

A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

Metastatic melanoma has a high mortality rate due to lymphatic progression of the disease. Current treatment is surgery followed by radiation and intravenous chemotherapy. However, drawbacks for current chemotherapeutics lie in the fact that they develop resistance and do not achieve therapeutic concentrations in the lymphatic system. We hypothesize that a three-drug nanoscale drug delivery system, tailored for lymphatic uptake, administered subcutaneously, will have decreased drug resistance and therefore offer better therapeutic outcomes. We prepared and characterized nanoparticles (NPs) with docetaxel, everolimus, and LY294002 in polyethyleneglycol-block-poly(ε-caprolactone) (PEG-PCL) polymer with different charge distributions by modifying the ratio of anionic and neutral end groups on the PEG block. These NPs are similarly sized (~48nm), with neutral, partially charged, or fully charged surface. The NPs are able to load ~2mg/mL of each drug and are stable for 24h. The NPs are assessed for safety and efficacy in two transgenic metastatic melanoma mouse models. All the NPs were safe in both models based on general appearance, weight changes, death, and blood biochemical analyses. The partially charged NPs are most effective in decreasing the number of melanocytes at both the proximal (sentinel) lymph node (LN) and the distal LN from the injection site. The neutral NPs are efficacious at the proximal LN, while the fully charged NPs have no effect on either LNs. Thus, our data indicates that the NP surface charge and lymphatic efficacy are closely tied to each other and the partially charged NPs have the highest potential in treating metastatic melanoma

Engineering nanoparticles for targeting rheumatoid arthritis: Past, present, and future trends

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial joint inflammation and cartilage and bone tissue destruction. Although there exist some treatment strategies for RA, they are not completely safe and effective. Therefore, it is important to develop and test new drugs for RA that specifically target inflamed/swollen joints and simultaneously attenuate other possible damages to healthy tissues. Nanotechnology can be a good alternative to consider when envisioning precise medication for treating RA. Through the use of nanoparticles, it is possible to increase bioavailability and bioactivity of therapeutics and enable selective targeting to damaged joints. Herein, recent studies using nanoparticles for the treatment of RA, namely with liposomes, polymeric nanoparticles, dendrimers, and metallic nanoparticles, have been reviewed. These therapeutic strategies have shown great promise in improving the treatment over that by traditional drugs. The results of these studies confirm that feasibility of the use of nanoparticles is mainly due to their biocompatibility, low toxicity, controlled release, and selective drug delivery to inflamed tissues in animal RA models. Therefore, it is possible to claim that nanotechnology will, in the near future, play a crucial role in advanced treatments and patient-specific therapies for human diseases such as RA.Financial support under the ARTICULATE project (No. QREN-13/SI/2011-23189). This study was also funded by the Portuguese Foundation for Science and Technology (FCT) project OsteoCart (No. PTDC/CTM-BPC/115977/2009), as well as the European Union’s FP7 Programme under grant agreement no REGPOT-CT2012-316331-POLARIS. The FCT distinction attributed to J. M. O. under the Investigator FCT program (No. IF/00423/2012) is also greatly acknowledged. C. G. also wished to acknowledge FCT for supporting her research (No. SFRH/BPD/94277/2013)info:eu-repo/semantics/publishedVersio

Nanoparticles: Emerging carriers for drug delivery

AbstractThe core objective of nanoparticles is to control and manipulate biomacromolecular constructs and supramolecular assemblies that are critical to living cells in order to improve the quality of human health. By definition, these constructs and assemblies are nanoscale and include entities such as drugs, proteins, DNA/RNA, viruses, cellular lipid bilayers, cellular receptor sites and antibody variable regions critical for immunology and are involved in events of nanoscale proportions. The emergence of such nanotherapeutics/diagnostics will allow a deeper understanding of human longevity and human ills that include cancer, cardiovascular disease and genetic disorders. A technology platform that provides a wide range of synthetic nanostructures that may be controlled as a function of size, shape and surface chemistry and scale to these nanotechnical dimensions will be a critical first step in developing appropriate tools and a scientific basis for understanding nanoparticles

Characterization and toxicity of citral incorporated with nanostructured lipid carrier

The nanoparticle as a cancer drug delivery vehicle is rapidly under investigation due to its promising applicability as a novel drug delivery system for anticancer agents. This study describes the development, characterization and toxicity studies of a nanostructured lipid carrier (NLC) system for citral. Citral was loaded into the NLC using high pressure homogenization methods. The characterizations of NLC-citral were then determined through various methods. Based on Transmission Electron Microscope (TEM) analysis, NLC-Citral showed a spherical shape with an average diameter size of 54.12 ± 0.30 nm and a polydipersity index of 0.224 ± 0.005. The zeta potential of NLC-Citral was −12.73 ± 0.34 mV with an entrapment efficiency of 98.9 ± 0.124%, and drug loading of 9.84 ± 0.041%. Safety profile of the formulation was examined via in vitro and in vivo routes to study its effects toward normal cells. NLC-Citral exhibited no toxic effects towards the proliferation of mice splenocytes. Moreover, no mortality and toxic signs were observed in the treated groups after 28 days of treatment. There were also no significant alterations in serum biochemical analysis for all treatments. Increase in immunomodulatory effects of treated NLC-Citral and Citral groups was verified from the increase in CD4/CD3 and CD8/CD3 T cell population in both NLC-citral and citral treated splenocytes. This study suggests that NLC is a promising drug delivery system for citral as it has the potential in sustaining drug release without inducing any toxicity