Medicinal Chemistry

Effective drug delivery systems require controlled drug release at the target cancer cell. While strategies for targeting tumors have been extensively studied, a better understanding of the necessary technology for controlling the spatiotemporal release of a drug is still needed. It has been established that the use of light can be a unique tool for controlling drug release. While UV light can be used for the release of biologically active, caged (deactivated) compounds, clinical application is restricted because of its limited ability to penetrate tissues as well as its cytotoxicity. Recently, the use of both tissue-penetrable visible and near IR have shown promise to overcome these limitations. In this short review, we introduce new smart strategies to convert such low energy light to a tissue-penetrable stimulus for both actively and remotely controlling drug release.

An adduct, namely (S)-4-acetamido-N-(2-(N-benzyloxycarbonyl- glycylprolyl)aminophenyl)benzamide (Z-GPCI- 994) has been designed and synthesized. All the evidences disclose that Z-GP-CI-994 is not the substrate of fibroblast activation protein-α (FAPα). However, the adduct is the substrate of another unknown enzyme which is ubiquitous in tumor tissue. The cytotoxicity of the adduct against HepG2, A549 and NIH3T3 cell lines is apparently decreased when compared to that of the parent compound (CI-994). Additionally, the inhibition rate of Z-GP-CI-994 on histone deacetylase is significantly lower than that of CI-994. All the results suggest preliminarily that Z-GP-CI-994 is promising to achieve enzyme-targeting delivery and to reduce systemic toxicity.

The present study was undertaken to investigate the effects of novel CF3-(MIF-1) analogue on stress-induced analgesia after restraint and cold stress in rats. The analgesic effect of CF3-(MIF-1) has been evaluated by paw pressure (PP) and hot plate (HP), and compared to the native tripeptide MIF-1. Our hypothesis was that incorporation of the trifluoromethyl group (CF3) in the novel MIF-1 analogue molecule would increase its antagonizing effect in both tests and after both kinds of stress compared to the native tripeptide MIF-1.

The results obtained showed that both the non-fluorinated and the fluorinated peptides significantly decreased SIA in PP and HP tests during the whole investigated period and CF3-(MIF-1) had a stronger anti-opioid effect compared to MIF-1.

Introduction: Gemcitabine is a pyrimidine nucleoside analog that becomes triphosphorylated and competitively inhibits cytidine incorporation into DNA strands. Diphosphorylated gemcitabine irreversibly inhibits ribonucleotide reductase thereby preventing deoxyribonucleotide synthesis. Functioning as a potent chemotherapeutic, gemcitabine decreases neoplastic cell proliferation and induces apoptosis which accounts for its effectiveness in the clinical treatment of several leukemia and carcinoma cell types. A brief plasma half-life due to rapid deamination, chemotherapeuticresistance and sequelae restrict gemcitabine utility in clinical oncology. Selective “targeted” gemcitabine delivery represents a molecular strategy for prolonging its plasma half-life and minimizing innocent tissue/organ exposure.

Methods: A previously described organic chemistry scheme was applied to synthesize a UV-photoactivated gemcitabine intermediate for production of gemcitabine-(C4-amide)-[anti-HER2/neu]. Immunodetection analysis (Western-blot) was applied to detect the presence of any degradative fragmentation or polymerization. Detection of retained binding-avidity of gemcitabine-(C4-amide)-[anti-HER2/neu] was determined by cell-ELISA using populations of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) that highly over-express the HER2/neu trophic membrane receptor. Cytotoxic anti-neoplastic potency of gemcitabine-(C4-amide)-[anti-HER2/neu] and the tubulin/ microtubule inhibitor, griseofulvin was established against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3). Related investigations evaluated the potential for gemcitabine-(C4-amide)-[anti-HER2/neu] in dual combination with griseofulvin to evoke increased levels of cytotoxic anti-neoplatic potency compared to gemcitabine- (C4-amide)-[anti-HER2/neu].

Results: Covalent gemcitabine-(C4-amide)-[anti-HER2/neu] immunochemotherapeutic and griseofulvin exerted cytotoxic anti-neoplastic potency against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3). Covalent gemcitabine-(C4-amide)-[anti-HER2/neu] immunochemotherapeutic or gemcitabine in dual combination with griseofulvin created increased levels of cytotoxic anti-neoplastic potency that were greater than was attainable with gemcitabine-(C4-amide)-[anti-HER2/neu] or gemcitabine alone.

Conclusion: Gemcitabine-(C4-amide)-[anti-HER2/neu] in dual combination with griseofulvin can produce enhanced levels of cytotoxic anti-neoplastic activity and potentially provide a basis for treatment regimens with a wider marginof- safety. Such benefits would be possible through the collective properties of; [i] selective “targeted” gemcitabine delivery; [ii] relatively lower toxicity of griseofulvin compared to many if not most conventional chemotherapeutics; [iii] reduced total dosage requirements faciliated by additive or synergistic anti-cancer properties; and [iv] differences in sequelae for gemcitabine-(C4-amide)-[anti-HER2/neu] compared to griseofulvin functioning as a tubulin/microtubule inhibitor.

The invasive species of Pterois volitans or commonly known as the lionfish, is spread throughout the sub-tropical and tropical Western Atlantic. The lionfish species have begun to rise as a very successful intrusive predator. Their invasion of coral reef ecosystems is a major conservation concern. Many studies have shown that this top coral reef predator is able to reproduce quickly, it’s able to survive better in foreign waters than in its native location, and it lacks significant predators when fully matured. These fish are commonly found in shallow waters with rocks or reefs, and are easily recognizable by their elegant plume-like fins.

The defensive mechanism of the lionfish proves to be quite successful due to its venomous spines projecting from its body. The spines produce a combination of protein, a neuromuscular toxin and a neurotransmitter called acetylcholine. To humans the venomous sting can cause extreme pain, sweating, respiratory problems, and sometimes paralysis if stung severely. However, these invasive species could provide an alternate medicine or use with their venom to control MRSA.

Methicillin-resistant Staphylococcus aureus (MRSA) a resistant microbe that can withstand first-line antibiotics. MRSA infections account for many of the “staph” infections around the world and can also be fatal as well if not treated quickly. MRSA infections are resistant to most antibiotics though it can be treated with the powerful antibiotics, vancomycin and teicoplanin. Because the oral absorption of these drugs is low, these agents must be administered intravenously to control systemic infections. Though, the properties of the lionfish venom may prove to be an alternative to control the growth of MRSA.

This experiment is designed to test the effectiveness of the venom extracted from the lionfish as an alternative medicine to controlling or hindering the growth of the bacterium MRSA when applied to the infected area. The efficiency of the isolated venom was evaluated by looking at the growth rates of the different colonies of MRSA were treated with the venom. The venom proved to not hinder the growth of the MRSA bacteria a significant amount.

A series of aryl azonaphthoquinones 8a-e were obtained via coupling of the corresponding diazonium salts 7a-c with naphthoquinones 2 or 3 in pyridine. Moreover, treatment of 5 with 6a, b in ethanol containing potassium carbonate afforded the corresponding enaminones 9a, b, respectively. Furthermore, heating of 6a with 2-hydroxy-3-((piperidn- 1-yl)methyl)naphthalene-1,4-dione 10 in EtOH/AcOHor sodium 3,4-dihydro-3,4-dioxonaphthalene-1-sulphonate 1 in MeOH/H2O afforded the corresponding enaminones 11 and 12, respectively. The newly synthesized compounds were screened for their antioxidant activity. Compounds 8b 89.87, 9a (89.93%) and 9b (95.97%) exhibited promising activities. On the other hand compounds 8b, 9a, 9b, 11 and 12 have the ability to protect DNA from the damage induced by bleomycin.