Abstract
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 (IC50 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.
Highlights
Leukemia is a blood or bone marrow cancer characterized by an uncontrolled hematopoiesis process [1]
Cyclic-endoporoxide natural products are very rare, and this is the first report of withasteroid-endoperoxides from Withania genus, suggesting that the enzymatic system in W. aristata is quite different to other Withania species
Biological evaluation and in silico ADME exploration revealed that four compounds from this series are promising anti-leukemic agents, showing higher effectiveness than the known chemotherapeutic drug etoposide
Summary
Leukemia is a blood or bone marrow cancer characterized by an uncontrolled hematopoiesis process [1]. Acute myeloid leukemia (AML) is a genetically heterogeneous disease that has a poor prognosis and is the most common leukemia in adults. Its incidence has increased dramatically in highly developed regions of the world. AML involves the abnormal proliferation and differentiation of a clonal population of the myeloid stem as a consequence of mutations in the genes implicated in these processes [2] and epigenetic changes [3]. In acute promyelocytic leukemia (APL), the formation of chimeric proteins such as RUNX1-RUNX1T1 and PML-RARA alter the normal maturation process of myeloid precursor cells [4]. Present-day standard intervention for leukemia consists of chemotherapy and stem cell transplantation [5]. Current chemotherapeutic drugs cause a range of side effects and Molecules 2020, 25, 5744; doi:10.3390/molecules25235744 www.mdpi.com/journal/molecules
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