Hybrids of Steroid and Nitrogen Mustard as Antiproliferative Agents: Synthesis, In Vitro Evaluation and In Silico Inverse Screening

Abstract

Hybrids of 16E-arylidene steroids and nitrogen mustard have been synthesized and evaluated for their in vitro cytotoxic activity to develop tissue specific antineoplastic agents from steroids. These hybrids displayed specificity towards leukemia cell lines, however somewhat reduced potency was observed in comparison with the earlier reported 16E-arylidene steroids. The in silico reverse screening experiments were employed to find out the probable pharmacological mechanism of these hybrids. Molecular docking studies suggested glucocorticoid receptors as a probable target for the antileukemic action of these steroid-nitrogen mustard hybrids.

Highlights on Steroidal Arylidene Derivatives as a Source of Pharmacologically Active Compounds: A Review

“…Despite these promising results, other studies carried out with 2- and 16 E -arylideneandrostrane derivatives were described, but less relevant biological effects were observed [ 17 , 38 , 50 , 55 , 64 , 67 ]. In addition, Semenenko and coworkers prepared 16 E -arylidenedehydroepiandrosterones, as well as 2-arylidenesteroidal derivatives of cholestanone, to be used as chiral dopants for cholesteric liquid crystal composition [ 74 ].…”

“…However, the specificity of these compounds towards leukemia cells still remains unaffected and reduced potency was observed when compared to earlier reports for 16 E -arylidene steroids [ 61 , 62 ]. Further studies suggested that these derivatives present different mechanisms of action in leukemia cells [ 17 ]. More recently, Brito et al reported the synthesis, antiproliferative effects, and in silico studies of novel 16 E -arylidene-4-azaandrost-5-enes as prostate cell growth inhibitors.…”

“…In fact, even a minor structural variation on the steroidal nucleus can lead to marked changes in their physiological activity [ 15 ]. Therefore, aiming to improve their pharmacological properties and/or develop compounds with different bioactivities, structural modifications of steroids have been an important focus of research over the last decades [ 16 , 17 , 18 , 19 , 20 ].…”

“…Moreover, the presence and inherent reactivity of their α,β-unsaturated ketone system can also be associated with potential toxicity problems, including mutagenesis and carcinogenesis [ 31 , 32 ]. Despite this, over the years, various arylidenesteroids have been studied, namely as hydroxysteroid dehydrogenases, aromatase, and 5α-reductases inhibitors, as well as skeletal muscle relaxants, antimicrobial, neuroprotective, antiparasitic, and antiproliferative agents [ 17 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. Additionally, other research works have been demonstrating their use as synthetic intermediates, mainly in the preparation of aza-heterocycles with relevant potential applications [ 41 , 42 ].…”

Stereoselective Synthesis of Spirooxindole Derivatives Using One-Pot Multicomponent Cycloaddition Reaction and Evaluation of Their Antiproliferative Efficacy

“…The search for a cancer chemotherapeutic agent with better efficacy and less toxicity endures a challenge for a new drug discovery process and has always compelled medicinal chemists to discover innovative agents with cancer selectivity . Isatin-inspired spirooxindole derivatives are a highly precious synthetic framework due to their diversified biological properties including the antiproliferative activity. , Spirooxindoles are found in several bioactive natural products such as coerulescine, horsfiline, spirotryprostatin A, welwitindolinone A, elacomine, and alstonisine .…”