Withanolide-Type Steroids from Withania aristata as Potential Anti-Leukemic Agents

Leukemia is a blood or bone marrow cancer with increasing incidence in developed regions of the world. Currently, there is an ongoing need for novel and safe anti-leukemic agents, as no fully effective chemotherapy is available to treat this life-threatening disease. Herein, are reported the isolation, structural elucidation, and anti-leukemic evaluation of twenty-nine withanolide-type steroids (1–29) from Withania aristata. Among them, the new isolated withanolides, withaperoxidins A–D (1–4) have an unusual six-membered cyclic peroxide moiety on the withasteroid skeleton as a structural novelty. Their structures have been elucidated by means of spectroscopic analyses, including 2D NMR experiments. In addition, extensive structure–activity relationships and in silico ADME studies were employed to understand the pharmacophore and pharmacokinetic properties of this series of withasteroids. Compounds 15, 16, and 22 together with withaferin A (14) were identified as having improved antiproliferative effect (IC(50) ranging from 0.2 to 0.7 μM) on human leukemia HL-60 cell lines compared with the reference drug, etoposide. This cytotoxic potency was also coupled with good selectivity index (SI 33.0–9.2) on non-tumoral Vero cell line and in silico drug likeness. These findings revealed that these natural withasteroids are potential candidates as chemotherapeutic agents in the treatment of leukemia.