Abstract
Development of novel anticancer therapeutic candidates is one of the key challenges in medicinal chemistry. Podophyllotoxin and its derivatives, as a potent cytotoxic agent, have been at the center of extensive chemical amendment and pharmacological investigation. Herein, a new series of podophyllotoxin-N-sulfonyl amidine hybrids (4a–4v, 5a–5f) were synthesized by a CuAAC/ring-opening procedure. All the synthesized podophyllotoxins derivatives were evaluated for in vitro cytotoxic activity against a panel of human lung (A-549) cancer cell lines. Different substituents’, or functional groups’ antiproliferative activities were discussed. The –CF3 group performed best (IC50: 1.65 μM) and exhibited more potent activity than etoposide. Furthermore, molecular docking and dynamics studies were also conducted for active compounds and the results were in good agreement with the observed IC50 values.
Highlights
Podophyllotoxin is a potent cytotoxic agent and serves as a useful lead compound for the development of drugs due to its cytotoxic, insecticidal, antifungal, antiviral, anti-inflammatory, neurotoxic, immunosuppressive, antirheumatic, antioxidative, anti-spasmogenic, and hypolipidemic activities
Similar to etoposide [6], teneposide [7] drugs have been proven to be potential antitumor drugs in clinical use; NPF [8] and GL-331 [9] have been under clinical trials
Their therapeutic efficacy is often limited to their undesirable secondary effects, for example, gastrointestinal toxicity, neurotoxicity, hair loss, bone marrow suppression, etc., as well as the development of resistance by cancer cells [3]
Summary
Podophyllotoxin is a potent cytotoxic agent and serves as a useful lead compound for the development of drugs due to its cytotoxic, insecticidal, antifungal, antiviral, anti-inflammatory, neurotoxic, immunosuppressive, antirheumatic, antioxidative, anti-spasmogenic, and hypolipidemic activities. Similar to etoposide [6], teneposide [7] drugs have been proven to be potential antitumor drugs in clinical use; NPF [8] and GL-331 [9] have been under clinical trials. Their therapeutic efficacy is often limited to their undesirable secondary effects, for example, gastrointestinal toxicity, neurotoxicity, hair loss, bone marrow suppression, etc., as well as the development of resistance by cancer cells [3]. The development of less toxic derivatives or analogues has been a consistent focus of podophyllotoxin modifications.
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