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.

Dietary Niche and Growth Rate of the Nonnative Tubenose Goby (Proterorhinus semilunaris) in the Lake Superior Basin.

The tubenose goby (Proterorhinus semilunaris) entered the Great Lakes in the 1990s via ballast water, but remains poorly studied within North America, making it difficult to predict its effects on native ecosystems. Dietary breadth and somatic growth rate have important ramifications for survival, competitiveness, and dispersal ability of a fish species, and thereby its ecological impact. We studied diet and growth of age-0 tubenose goby within the St. Louis River, a tributary to Lake Superior that contains the largest population within the Lake Superior basin. We sampled tubenose gobies from shallow, vegetated habitat during summer and fall. Stomach contents were identified and weighed to measure fullness and dietary breadth between seasons and several locations. We aged fish based on otolith daily increments to model somatic growth. Diet was dominated by isopods and amphipods, and dietary breadth was low and not significantly different between locations and seasons. Tubenose goby diet strongly overlapped with that of tadpole madtom (Noturus gyrinus), a native, demersal species. We tested several candidate growth models; the Gompertz Growth Function was the most parsimonious model among those examined. The model demonstrates that tubenose goby obtains a small maximum size and is short-lived. We conclude that tubenose goby presents a unique risk to the Great Lakes and other freshwater bodies because their life history is typical of invasive species, their diet overlaps with native fish, and because they occupy shallow, vegetated habitat which functions as both nursery and foraging habitat for many native fishes.