Development of Bexarotene Analogs for Treating Cutaneous T-Cell Lymphomas.

Bexarotene, a drug approved for treatment of cutaneous T-cell lymphoma (CTCL), is classified as a rexinoid by its ability to act as a retinoid X receptor (RXR) agonist with high specificity. Rexinoids are capable of inducing RXR homodimerization leading to the induction of apoptosis and inhibition of proliferation in human cancers. Numerous studies have shown that bexarotene is effective in reducing viability and proliferation in CTCL cell lines. However, many treated patients present with cutaneous toxicity, hypothyroidism, and hyperlipidemia due to crossover activity with retinoic acid receptor (RAR), thyroid hormone receptor (TR), and liver X receptor (LXR) signaling, respectively. In this study, 10 novel analogs and three standard compounds were evaluated side-by-side with bexarotene for their ability to drive RXR homodimerization and subsequent binding to the RXR response element (RXRE). In addition, these analogs were assessed for proliferation inhibition of CTCL cells, cytotoxicity, and mutagenicity. Furthermore, the most effective analogs were analyzed via qPCR to determine efficacy in modulating expression of two critical tumor suppressor genes, ATF3 and EGR3. Our results suggest that these new compounds may possess similar or enhanced therapeutic potential since they display enhanced RXR activation with equivalent or greater reduction in CTCL cell proliferation, as well as the ability to induce ATF3 and EGR3. This work broadens our understanding of RXR-ligand relationships and permits development of possibly more efficacious pharmaceutical drugs. Modifications of RXR agonists can yield agents with enhanced biological selectivity and potency when compared to the parent compound, potentially leading to improved patient outcomes.

Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB).

Five novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid-or NEt-4IB-in addition to seven novel analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene (1), a FDA-approved drug for cutaneous T-cell lymphoma (CTCL). Bexarotene treatment elicits side-effects by provoking or disrupting other RXR-dependent pathways. Analogs were assessed by the modeling of binding to RXR and then evaluated in a human cell-based RXR-RXR mammalian-2-hybrid (M2H) system as well as a RXRE-controlled transcriptional system. The analogs were also tested in KMT2A-MLLT3 leukemia cells and the EC50 and IC50 values were determined for these compounds. Moreover, the analogs were assessed for activation of LXR in an LXRE system as drivers of ApoE expression and subsequent use as potential therapeutics in neurodegenerative disorders, and the results revealed that these compounds exerted a range of differential LXR-RXR activation and selectivity. Furthermore, several of the novel analogs in this study exhibited reduced RARE cross-signaling, implying RXR selectivity. These results demonstrate that modification of partial agonists such as NEt-4IB and potent rexinoids such as bexarotene can lead to compounds with improved RXR selectivity, decreased cross-signaling of other RXR-dependent nuclear receptors, increased LXRE-heterodimer selectivity, and enhanced anti-proliferative potential in leukemia cell lines compared to therapeutics such as 1.

The Effect of Lauric Acid on Pathogens Colonizing the Burn Wound: A Pilot Study.

OBJECTIVE: Some of the most serious complications of burns include septic infections. Instead of fulfilling the function of a protective barrier, tissues damaged by high temperature create a niche that serves as an environment and source of nourishment for pathogens. An accepted practice is to use antibiotics to inhibit development of pathogens. Taking into consideration the characteristics of the burn wound and increasing antibiotic resistance, the search for new substances that have both antimicrobial and regenerative effects seems justified. The aim of the study was to determine the influence of lauric acid on bacteria-colonizing tissue samples taken during surgical treatment of burns. METHODS: Lauric acid was combined with 5 different ointment bases: Anhydrous Eucerin DAB, Anhydrous Eucerin II, Hydrophilic Vaseline, White Vaseline, and Lekobaza. The content of lauric acid in the ointment bases was 10% to 20% w/w. The preparations were applied onto samples of burnt skin collected during surgery. The samples were subsequently subjected to a microbiological test with the use of model strains of Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli. RESULTS: With one exception (White Vaseline), lauric acid showed a more pronounced effect on bacteria in 20% w/w concentration. In a 10% lauric acid concentration, no effect on bacteria was observed on the Hydrophilic Vaseline ointment base. Lauric acid had the strongest inhibiting effect on microbial growth of Gram-positive Staphylococcus aureus. Satisfactory zones of inhibition were also observed in the case of Escherichia coli. Growth inhibition of Pseudomonas aeruginosa was observed only when pure lauric acid was used. CONCLUSIONS: Due to its aseptic and regenerative effect on chemically damaged tissues, lauric acid can be a promising modifier of the burn healing process.