Overcoming Solubility Challenges: Liposomal isoCoQ-Carbazole as a Promising Anti-Tumor Agent for Inoperable and Radiation-Insensitive cancers.

This study evaluated the potential of isoCoQ-Carbazole, a diheterocyclic analog of isoCA-4, as an anti-tumor agent. To overcome its low aqueous solubility, liposomes were developed as a delivery system for the compound. In vitro experiments showed that loaded liposomes exhibited similar activity to the free form on multiple human tumor cell lines. In vivo experiments using a palliative intratumoral injection chemotherapy approach further demonstrated that isoCoQ-Carbazole loaded liposomes significantly reduced tumor growth in a CA-4-resistant HT29 cell model, without inducing any observable toxicity or weight loss in the treated mice. These findings suggest that liposomal isoCoQ-Carbazole may hold promise as a potential therapeutic agent for the treatment of inoperable, radiation-insensitive cancers.

[Topical treatment for age-related macular degeneration: Where are we now?] / Traitement topique de la dégénérescence maculaire liée à l'âge - Où en sommes-nous ?

The therapeutic management of age-related macular degeneration (AMD) is a major public health issue. One of its two late forms, neovascular AMD, is currently treated by intravitreal injections of pharmaceutical active ingredients. Although it is very effective in treating pathologies of the posterior segment of the eye, the intravitreal route is not an ideal option for the long-term management of a chronic disease such as AMD. Indeed, in the literature, some authors even call it a "burden" for the practitioners, the patients and the healthcare system. Thus, consideration should be given to less invasive routes. Among the possible administration routes to reach the posterior segment of the eye, the most suitable for the patient with the least risk of systemic adverse effects is the topical route. Several research teams have attempted to formulate molecules for topical administration in the treatment of atrophic or neovascular AMD. In this review, we emphasize the importance of the pharmaceutical formulation to meet the challenge of targeting the posterior segment of the eye by a topical route.

Title: Traitement topique de la dégénérescence maculaire liée à l'âge - Où en sommes-nous ? Abstract: La prise en charge thérapeutique de la dégénérescence maculaire liée à l'âge (DMLA) est un enjeu majeur de santé publique. L'une de ses deux formes tardives, la DMLA néovasculaire, est actuellement traitée par injection intravitréenne de molécules anti-angiogéniques. Bien qu'elle soit très efficace pour traiter les atteintes du segment postérieur de l'œil, la voie intravitréenne n'est pas une option idéale pour la prise en charge au long cours d'une maladie chronique telle que la DMLA. L'administration topique de molécules actives contre cette maladie, plus confortable pour le patient et moins coûteuse pour la société, représente un vrai défi.

Recent Advances in Age-Related Macular Degeneration Therapies.

Age-related macular degeneration (AMD) was described for the first time in the 1840s and is currently the leading cause of blindness for patients over 65 years in Western Countries. This disease impacts the eye's posterior segment and damages the macula, a retina section with high levels of photoreceptor cells and responsible for the central vision. Advanced AMD stages are divided into the atrophic (dry) form and the exudative (wet) form. Atrophic AMD consists in the progressive atrophy of the retinal pigment epithelium (RPE) and the outer retinal layers, while the exudative form results in the anarchic invasion by choroidal neo-vessels of RPE and the retina. This invasion is responsible for fluid accumulation in the intra/sub-retinal spaces and for a progressive dysfunction of the photoreceptor cells. To date, the few existing anti-AMD therapies may only delay or suspend its progression, without providing cure to patients. However, in the last decade, an outstanding number of research programs targeting its different aspects have been initiated by academics and industrials. This review aims to bring together the most recent advances and insights into the mechanisms underlying AMD pathogenicity and disease evolution, and to highlight the current hypotheses towards the development of new treatments, i.e., symptomatic vs. curative. The therapeutic options and drugs proposed to tackle these mechanisms are analyzed and critically compared. A particular emphasis has been given to the therapeutic agents currently tested in clinical trials, whose results have been carefully collected and discussed whenever possible.

Design, synthesis and biological evaluation of quinoline-2-carbonitrile-based hydroxamic acids as dual tubulin polymerization and histone deacetylases inhibitors.

A series of quinoline and quinazoline analogs were designed and synthesized as new tubulin polymerization (TP) and histone deacetylases (HDAC) inhibitors. Compounds 12a and 12d showed the best cytotoxicity activities against a panel of human cancer cell lines with an averaged IC50 value of 0.6 and 0.7 nM, respectively. Furthermore, these lead compounds showed good activities against CA-4-resistant colon-carcinoma and multidrug-resistant leukemia cells. In addition, compounds 12a and 12d induced HT29 cell cycle arrest in the G2/M phase and produced caspase-induced apoptosis of HT29 cells through mitochondrial dysfunction. Also, 12a and 12d inhibited HDAC8, 6, and 11 activities. Furthermore, lead compound 12a exhibited higher metabolic stability than isoCA-4 and was highly potent in suppressing tumor growth in the fibrosarcoma MCA205 tumor model. Collectively, these studies suggest that 12a represents a new dual inhibitor of TP and HDAC activities, which makes it a suitable candidate for further investigations in clinical development.

Photoredox synthesis of 6- and 7-membered ring scaffolds via N-centered radicals.

N-Containing heterocycles are important scaffolds due to their ubiquitous presence in bioactive compounds. Their synthesis has been considered as an important research field. In this work we report the access to 6- and 7-membered rings via a photoinduced strategy. To our knowledge, this work represents the first exemple of photo-induced 7-endo-trig cyclization with N-centered radicals.

Sequential One-Pot Synthesis of 3-Arylbenzofurans from N-Tosylhydrazones and Bromophenol Derivatives.

A divergent and efficient one-pot sequence allowing direct access to 3-arylbenzofuran derivatives has been developed. The process, involving N-tosylhydrazones and bromophenols, proceeds via a palladium-catalyzed Barluenga-Valdés cross-coupling, followed by an aerobic, copper-catalyzed, radical cyclization to form Csp2-Csp2 and O-Csp2 bonds. 3-Arylated benzofurans bearing various substituents were obtained with good to excellent yields (up to 90%). Mechanistic investigation strongly supports a radical process for the cyclization step.

Toward a Greener Barluenga-Valdés Cross-Coupling: Microwave-Promoted C-C Bond Formation with a Pd/PEG/H2O Recyclable Catalytic System.

A green Barluenga-Valdés cross-coupling reaction for the synthesis of 1,1-diarylethylenes using palladium catalysis has been developed. The new catalytic system based on Pd/Xphos-SO3Na or Pd/MeDavephos-CF3SO3 in PEG/H2O under microwave irradiation was found to be the best conditions for this transformation. The recyclability of the palladium catalyst system was also studied, and it was found to be active over nine runs without significant loss in its activity.

Design and Synthesis of Tubulin and Histone Deacetylase Inhibitor Based on iso-Combretastatin A-4.

Designing multitarget drugs have raised considerable interest due to their advantages in the treatment of complex diseases such as cancer. Their design constitutes a challenge in antitumor drug discovery. The present study reports a dual inhibition of tubulin polymerization and HDAC activity. On the basis of 1,1-diarylethylenes ( isoCA-4) and belinostat, a series of hybrid molecules was successfully designed and synthesized. In particular compounds, 5f and 5h were proven to be potent inhibitors of both tubulin polymerization and HDAC8 leading to excellent antiproliferative activity.

Csp2-Csp2 and Csp2-N Bond Formation in a One-Pot Reaction between N-Tosylhydrazones and Bromonitrobenzenes: An Unexpected Cyclization to Substituted Indole Derivatives.

A novel, sequential, palladium-catalyzed, cross-coupling reaction using N-tosylhydrazone and bromonitrobenzene derivatives followed by reductive cyclization has been developed. This transformation providing an efficient route to unexpected N-arylindole derivatives involves, in a one-pot reaction, the formation of one Csp2-Csp2 bond and two Csp2-N bonds together with the cleavage of one Csp2-heteroatom bond. Evaluation of the biological activity led to the identification of compound 5a, which displays potent activity at nanomolar concentrations against human colon carcinoma cell line.