Although, it is possible to discover new drug candidate molecules using in silico approaches, chemical synthesis and then screening for the function is still at the center of bioactive molecule discovery. While determining the potential effects of compounds to target the signaling molecules or pathways, assessing their effects on circadian rhythm is also very important because it controls most of the signaling pathways which may modulate the efficacy of drug candidates. It was here considered to prepare new members of the biocompatible cyclotriphosphazene family and evaluate their in vitro biological activities and effects on circadian rhythm for the first time. In this context, new cyclotriphosphazene derivatives carrying morpholine, thiomorpholine and triazole groups were designed, synthesized and their chemical structures were characterized by appropriate spectroscopic methods. Cellular toxicity analyses of the compounds were determined using different biological methods such as determination of IC50 values, calculation of population doubling times, and colony formation patterns. Subsequently, the effects of the compounds on cell cycle were analyzed by flow cytometry technique. Finally, the effects of the synthesized compounds on circadian rhythm were formed via real-time bioluminescence approach. At the end of the studies, it was determined that some compounds demonstrated varying degrees of antiproliferative activity, with the most potent compounds causing G2/M phase arrest. Additionally, most derivatives have no adverse effects on circadian rhythm, indicating potential for safe therapeutic application in targeting cell proliferation. Furthermore, an important pharmacological characteristic of the drug candidate molecules, namely membrane permeability in terms of LogP values, has
Design, synthesis and in vitro evaluations of new cyclotriphosphazenes as safe drug candidates
