Quaternary Phosphonium Salts Outperformed Vemurafenib (PLX) and Etoposide Against BRAF^{V600D, V600E} PLX-Resistant, Melanoma and MDR Neuroblastoma, Exhibiting No/Low Toxicity on 3T3/HaCaT Cells

Background. Late-stage metastatic cutaneous melanoma (MCM) and neuroblastoma (NB) are the most aggressive skin and childhood cancers with survival rate < 50%, mainly due to the emergence of resistance to available drugs, thus requiring urgent solution. Quaternary phosphonium salts (QPSs) can exhibit up to strong anticancer effects, regardless the developed resistances. Methods. Triphenyl (1) and diphenyl (3 and 4) phosphonium salts were synthesized, treating commercial triphenyl phosphine and synthesized 11-diphenylphosphanyl-undecan-1-ol (2) respectively, with benzyl bromide. Upon fully characterization, they were tested, for the first time, on MeTRAV (BRAFV600D) and MeOV (BRAFV600E) vemurafenib (PLX)-resistant MCM cells, etoposide (ETO)-sensitive (HTLA 230) and multidrug resistant (MDR) (HTLA ER) NB cells, not tumorigenic human keratinocytes (HaCaT) and mouse embryonic fibroblasts (3T3), as well as red blood cells (RBCs). Results and Discussion. Viability of MeTRAV cells was decreased to 44.8% by admin-istration of 1 (100 µM), in intermediate-time (48h) treatments, while short-time exposure (24h) to 3 (≥ 75 µM) and 4 (≥ 50 µM) was sufficient to reduce their viability to 33.6 and 32.2%. Viability of MeOV was decreased under 50% with 5 µM concentrations of 1 and 25 µM of 3 and 4, while were exterminated (26.9, 20.6 and 21.8%) with higher concentrations after 48h exposure. Collectively, 1 was the better performant compound (IC50 = 6.4 µM, 48h). Viability of HTLA ER cells was decreased under 50% upon 72h administrations of 1 at concentrations ≥ 50 µM, 48h (≥ 75 µM) and 72h (≥ 50 µM) of 3 and after 72h (≥ 75 µM) of 4, but 72-hours exposure and high concentrations of all compounds were necessary for their extermination (31.2, 28.7, 29.7%). Viability of HTLA 230 cells was not < 50% when 1 and 4 were administered for only 24h, while their viability was < 50% after administration of 3 at all-times exposure. At high concentrations all compounds exterminated cells (33.6, 25.3%, 1, 48-72h; 38.6, 30.2, 24.7%, 3, 24-72h; 33.2%, 4, 72h). The best performant compounds were 1 (IC50 = 4.0 µM, HTLA 230) and 3 (IC50 = 27.8 µM, HTLA ER) at 72h exposure. The cytotoxic effects of compound 4 on MeTRAV cells, when exposed to 24/48h treatments were comparable to those of PLX on same cells in 72h ones. 1, in shorter 48h treatments of PLX-R MeOV, was 2.5forl more cytotoxic than PLX in 72h ones. All compounds were no cytotoxic to 3T3 cells, at all time of exposure, low cytotoxic to HaCaT cells in 24 and 48h treatments and softly cytotoxic to RBCs in 24h ones. Conclusions. Compound 1 could be a promising platform to develop new intermediate-time therapies for PLX-R MeOV cells, while 4, to develop 24- and 48-hours treatments for PLX-R MeTRAV cells. Also, all compounds could be developed as new treatment options for both ETO-sensitive and MDR late-stage HR-NB cells, being all more effective than ETO by 1.2, 2.0, 1.3 times (HTLA 230) and 3.2, 4.7 and 3.2 times (HTLA ER). All compounds could be interesting to be developed as adjuvants in already existing anticancer cocktails to treat MCM and/or NB.