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Cancer remains one of the leading causes of death, worldwide. In addition, the lack of efficacy and selectivity of chemotherapeutic agents for cancer cells is a challenge that needs to be addressed through the development of new drugs. Since aminosteroids are of interest in fighting cancer, our group previously reported antiproliferative activity on several cancer cell lines of two representatives, RM-133 and RM-581. To extend the structure-activity relationship study of aminosteroids, of which RM-133 (androstane) and RM-581 (estrane) are the main candidates, we performed the chemical synthesis and biological evaluation on lung (SHP-77), breast (T-47D) and prostate (DU-145, PC-3 and LAPC-4) cancer cells of four analogues of RM-581. We moved the functionalized side chain from position 2 of the androstane and estrane derivatives to incorporate it into a new chain located at position 17. Chemical synthesis took place in 2 steps from steroidal side-chain carboxylic acids, allowing to obtain 4 steroid derivatives with acceptable yields, which were fully characterized by nuclear magnetic resonance spectroscopy ( 1 H and 13 C NMR). After the evaluation of compounds 12-15, lower antiproliferative activities varying from 12 to 54%, 0-33% and 0-63% were observed for SHP-77, DU-145 and PC-3 cell lines, respectively, while higher activities varying from 33 to 62% and 45-84% were observed for T-47D and LAPC-4 cell lines, respectively, when tested at 10 µM. Overall, it was observed that these aminosteroids have a lower cytotoxic activity than that of RM-581 and, that moving the side chain from steroid position C2 to C17 is clearly detrimental for antiproliferative activity. However, this work has enabled us to expand our knowledge of the structural requirements to maintain the anticancer activity of aminosteroid derivatives., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The high fatality and morbidity of pancreatic cancer have remained almost unchanged over the last decades and new clinical therapeutic tools are urgently needed. We determined the cytotoxic activity of aminosteroid derivatives RM-133 (androstane) and RM-581 (estrane) in three human pancreatic cancer cell lines (BxPC3, Hs766T and PANC-1). In PANC-1, a similar level of antiproliferative activity was observed for RM-581 and RM-133 (IC 50  = 3.9 and 4.3 μM, respectively), but RM-581 provided a higher selectivity index (SI = 12.8) for cancer cells over normal pancreatic cells than RM-133 (SI = 2.8). We also confirmed that RM-581 induces the same ER stress-apoptosis markers (BIP, CHOP and HERP) than RM-133 in PANC-1 cells, pointing out to a similar mechanism of action. Finally, these relevant in vitro results have been successfully translated in vivo by testing RM-581 using different doses (10-60 mg/kg/day) and modes of administration in PANC-1 xenograft models, which have led to tumor regression without any sign of toxicity in mice (animal weight, behavior and histology). Interestingly, RM-581 fully reduced the pancreatic tumor growth when administered orally in mice.