Conformationally constrained endo -configured KOR agonists were designed, synthesized and pharmacologically evaluated. The synthesis comprises 7 reaction steps. The endo -configured pyrrolidine shows high KOR affinity (NR ₂ = pyrrolidino: K _i = 7.0 nM).

Natural products are an excellent source of inspiration for the development of new drugs. Among them, betalains have been extensively studied for their antioxidant properties and potential application as natural food dyes. Herein, we describe the seven-step synthesis of new betalamic acid analogs without carboxy groups in the 2- and 6-position with an overall yield of ~70%. The Folin–Ciocalteu assay was used to determine the antioxidant properties of protected intermediate 21. Additionally, the five-step synthesis of betalamic acid analog 35 with three ester moieties was performed. Using NMR techniques, the stability of the obtained compounds towards oxygen was analyzed.

Ovarian and colorectal cancers have the highest incidence and mortality in the world, after breast cancer. Despite the initial response to Pt-drugs or 5-fluorouracil (5-FU), many cancer cells develop resistance to these drugs. For this reason, new therapeutic strategies represent an important medical need, in particular for drugs that are being studied in combination with methods that promote their entry into the cell. Among these strategies, electrochemotherapy (ECT), the combination of drugs with electroporation (EP), a physical method that uses high-frequency electrical pulses to create pores into which chemotherapy drugs can permeate, is gaining interest. In this study, we have evaluated the effect of ECT on the growth of both ovarian (A2780 and A2780/CP) and colorectal (HCT116) cancer cell lines using platinum derivatives (Cisplatin, Carboplatin and Oxaliplatin), as DNA alkylating agents, and human thymidylate synthase (hTS) inhibitors, both traditional (5FU) and novel TS destabilizers (compounds E3 and E7). To this aim, synergism quotient-like analysis to determine whether electroporation gives an advantage in terms of cytotoxicity was applied to the relative IC20 and IC50 concentrations of each drug. Results showed that two of the three Pt-drugs have greater efficacy when combined with EP. 5-FU and the new TS inhibitors E3 and E7 also take advantage of ECT because EP increases drug uptake into the cell, even in resistant cells. In conclusion, ECT appears to be a viable strategy to obviate the problem of resistance in ovarian and colorectal cancers, to deliver compounds inside cells overcoming uptake limits, especially for the low lipophilic compounds whose cytotoxic efficacy is hampered by the obstacle of biological membranes.