Atziri Corin Chavez Alvarez

Background/Objectives: To address current aggressive breast cancer challenges, a novel series of eight N-chalconyl imidazolidone derivatives (N-CIMZs 1–8) was synthesized and evaluated for direct cytotoxicity and immunomodulation via macrophage polarization. Methods: Following antiproliferative screening against four representative breast cancer lines, the prototype candidate N-CIMZ 1 was selected for cell cycle and scratch-wound healing assays in MCF-7 cells. Multi-parametric flow cytometry on human THP-1 macrophages tracked cellular stress (γH2AX), metabolic markers (iNOS), and surface dynamics (LAP (TGF-β1), CD163, CD206, CD209). Results: N-CIMZ 1 acted as an antimitotic agent, inducing G2/M phase arrest (51.0%) and restricting MCF-7 wound confluence to 33% at 24 h. In THP-1 macrophages, it maintained low induction of γH2AX-mediated DNA damage signaling. Under alternative M2 pressure, N-CIMZ 1 intercepted polarization by forcing high membrane retention of the immunosuppressive peptide LAP (81%) and suppressing the scavenger marker CD163 (12%) while buffering hyper-reactive CD206+/CD209+ hybrid spikes down to 2.33% under M1 stress. Conclusions: N-CIMZ 1 represents a promising multi-modal scaffold combining antimitotic and macrophage-modulating properties. This targeted immunomodulation effectively subverts tumor-supportive macrophage phenotypes, showcasing the potential of microenvironment reprogramming to counter breast cancer progression and metastasis.

Coumarin-based compounds are recognized for their chemical versatility and diverse biological activities, yet clinical applications remain largely confined to 4-hydroxycoumarin anticoagulants. To bridge this translational gap, coumarin scaffolds have been increasingly employed in prodrug design to enable controlled activation, targeted delivery, and theranostic functionality. This review critically evaluates whether coumarin-based prodrugs fulfill their therapeutic promise or remain primarily preclinical tools across oncology, inflammation, infectious diseases, and cardiovascular disorders. Strategies including enzymatic-, pH-, redox-, and light-triggered activation, as well as subcellular targeting and multifunctional hybrids, are discussed. Preclinical studies demonstrate improved bioavailability, reduced off-target toxicity, and real-time fluorescence monitoring, yet most compounds remain at the in vitro or small-animal model stage. Despite their mechanistic and conceptual potential, clinical translation is constrained by molecular complexity, pharmacokinetics, safety, and regulatory challenges. Overall, coumarins constitute a versatile multifunctional platform whose therapeutic impact relies on rigorous in vivo validation and strategic optimization.

Background/Objectives: Chronic inflammation underlies many immune-mediated conditions, yet current anti-inflammatory therapies are often limited by incomplete efficacy or safety concerns. Small molecules inspired by soluble epoxide hydrolase (sEH) inhibitors represent a promising scaffold for early-stage exploration. This study describes the design, synthesis, and preliminary biological evaluation of three series of arylurea derivatives (ACBUs) to establish structure–activity relationships and guide chemical optimization. Methods: The compounds were assessed for effects on keratinocyte proliferation, human sEH activity, and the expression of selected inflammatory markers using IL-17A/TNF-α-stimulated HaCaT cells, a relevant in vitro model for preliminary anti-inflammatory profiling. Results: A total of 23 novel ACBU derivatives were synthesized and evaluated. Most compounds showed low antiproliferative activity, allowing selection based on cytotoxicity and solubility. Compounds 4b, 10b, and 16b consistently displayed the most favorable profiles in these preliminary assays. Docking studies provided structural rationales supporting the observed trends and guided further optimization within the series. Conclusions: Compound 4b emerged as the most active candidate in preliminary screening, serving as a reference for ongoing SAR studies. These results highlight the potential of the arylurea scaffold for further chemical optimization and demonstrate the value of early-stage biological profiling in guiding our further studies.

A series of novel dihydroorotate dehydrogenase (DHODH) inhibitors designated as N-pyridinyl ureidobenzenesulfonates (PYRUB-SOs) and their hydrochloride salts were designed, synthesized, and evaluated for their biological activity.

Background/Objectives: Chemoresistance of breast cancers (BCs) is a major impediment to current chemotherapeutics that urges the development of new drugs and new therapeutic approaches. To that end, phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) were recently prepared to fulfill some of the unmet needs with classic chemotherapeutics. PAIB-SOs are prodrugs bioactivated into potent antimitotics by the cytochrome P450 1A1 (CYP1A1), which is a frequent enzyme in resistant BC cells, but mostly missing in normal cells. Our screening program studies of PAIB-SO chemolibraries selected three prototypical PAIB-SOs as antimitotic prodrugs amenable for studies using BC animal models. Methods: Healthy female CD1^® IGS mice were treated with three prototypical PAIB-SOs, namely CEU-835, -934, and -938, for the determination of their toxicity and half-lives. Moreover, MCF7 tumor-bearing CD1-Foxn1^nu Nude female mice were treated with the three prototypical PAIB-SOs for the determination of their antitumor activity. Results: Herein, we show that multi-intravenous administrations of CEU-835, -934, and -938 at their maximal solubilities are well tolerated in healthy female CD1^® IGS mice, as depicted by the evaluation of distress behaviors, organ necropsy, total blood cell count, and histology. Moreover, the half-life of CEU-835, -934, and -938 administered intravenously in healthy CD1^® IGS female mice were 8.1, 23.2, and 21.5 h, respectively. Finally, their intravenous administrations of CEU-934 and -938 decreased MCF7 tumor growth as efficiently as paclitaxel in MCF7 tumor-bearing CD1-Foxn1^nu Nude mouse model. Conclusions: overall, our study demonstrated for the first time that pentyl-bearing PAIB-SOs are new CYP1A1-dependent prodrugs efficiently decrease breast cancer tumor growth, and show no side effects at their pharmacological concentration in mouse models.

We developed first-in-class antimitotic prodrugs phenyl 4-(2-oxo-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) bioactivated by cytochrome P450 (CYP) 1A1 that are highly selective toward several breast cancer cells. However, they show sparingly water solubility. Therefore, we replaced their phenyl ring B with a substituted pyridinyl group preparing novel pyridinyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PYRAIB-SOs) and their hydrochloride salts. Our results evidence that PYRAIB-SO hydrochloride salts show higher water solubility compared to their neutral and PAIB-SO counterparts by up to 625-fold. PYRAIB-SOs with a nitrogen atom at position 3 of the pyridinyl ring exhibited strong antiproliferative activity (IC₅₀: 0.03–3.3 μM) and high selectivity (8–>1250) toward sensitive CYP1A1-positive breast cancer cells and cells stably transfected with CYP1A1. They induce cell cycle arrest in the G2/M phase and disrupt microtubule dynamic assembly. Enzymatic assays confirmed that CYP1A1 metabolizes PYRAIB-SOs into their active form with in vitro hepatic half-lives (55–120 min) in rodent and human liver microsomes. Overall, this will allow to increase drug concentration for in vivo studies.

Phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) are new antimitotic prodrugs bioactivated by the enzyme CYP1A1 into phenyl 4-(2-oxo-3-imidazolidin-1-yl)benzenesulfonates (PIB-SOs) that are potently (nM) and selectively inhibiting the growth of CYP1A1-expressing breast cancer cells. The screening program identified three PAIB-SOs designated as CEU-835, CEU-934, and CEU-938 for further pharmacokinetic studies. A novel method for their quantification in CD-1^® IGS female mouse plasma using a Waters UHPLC ACQUITY Arc system was developed and validated. Their analytical measurements ranged from 7.3 to 1484 ng/mL. They exhibited linearity between 7.3 and 1484 ng/mL. They also showed good resolutions (2.21–4.99) and good theoretical plate numbers (14707–70580). Moreover, they were robust at wavelengths between 273 and 310 nm and sensitive from 2 to 62 AU/ng mL⁻¹. This new method is indispensable to assess PAIB-SOs half-life in mouse plasma and for the quantification of PAIB-SOs in other biological matrices.

Phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) are a new family of antimitotic prodrugs bioactivated in breast cancer cells expressing CYP1A1. In this study, we report that the ¹⁴C-labeled prototypical PAIB-SO [¹⁴C]CEU-818 and its antimitotic counterpart [¹⁴C]CEU-602 are distributed in whole mouse body and they show a short half-life in mice. To circumvent this limitation, we evaluated the effect of the homologation of the alkyl side chain of the imidazolidin-2-one moiety of PAIB-SOs. Our studies evidence that PAIB-SOs bearing an n-pentyl side chain exhibit antiproliferative activity in the nanomolar-to-low-micromolar range and a high selectivity toward CYP1A1-positive breast cancer cells. Moreover, the most potent n-pentyl PAIB-SOs were significantly more stable toward rodent liver microsomes. In addition, PAIB-SOs 10 and 14 show significant antitumor activity and low toxicity in chorioallantoic membrane (CAM) assay. Our study confirms that homologation is a suitable approach to improve the rodent hepatic stability of PAIB-SOs.