Recent Advances in the Chemistry and Biology of Podophyllotoxins

Abstract

Podophyllotoxin and its related aryltetralin cyclolignans belong to a family of important products that exhibit various biological properties (e.g., cytotoxic, insecticidal, antifungal, antiviral, anti-inflammatory, neurotoxic, immunosuppressive, antirheumatic, antioxidative, antispasmogenic, and hypolipidemic activities). This Review provides a survey of podophyllotoxin and its analogues isolated from plants. In particular, recent developments in the elegant total chemical synthesis, structural modifications, biosynthesis, and biotransformation of podophyllotoxin and its analogues are summarized. Moreover, a deoxypodophyllotoxin-based chemosensor for selective detection of mercury ion is described. In addition to the most active podophyllotoxin derivatives in each series against human cancer cell lines and insect pests listed in the tables, the structure-activity relationships of podophyllotoxin derivatives as cytotoxic and insecticidal agents are also outlined. Future prospects and further developments in this area are covered at the end of the Review. We believe that this Review will provide necessary information for synthetic, medicinal, and pesticidal chemistry researchers who are interested in the chemistry and biology of podophyllotoxins.

Chemoenzymatic Total Synthesis of Deoxy‐, epi‐, and Podophyllotoxin and a Biocatalytic Kinetic Resolution of Dibenzylbutyrolactones

“…[15] Etoposide (5)t herefore became am ember of the WHOsl ist of essential medicines. [16] As other closely related compounds exhibit interesting bioactivities,too (e.g., cytotoxic, insecticidal, antifungal, antiviral, anti-inflammatory,n eurotoxic,i mmunosuppressive,a ntirheumatic, antispasmogenic,o rh ypolipidemic properties), [17] this structural motif has been the subject of several synthetic research endeavors.N evertheless,t he asymmetric construction of the yatein precursor (2a)a nd the stereoselective ring closure of ring Cs till represent major bottlenecks in the synthesis. Especially the construction of the southern stereocenter with the appropriate configuration has been remarkably difficult through the Friedel-Crafts approach, both chemically [18] and by biotechnological methods.…”

Semisynthesis of novel N‐acyl/sulfonyl derivatives of 5(3,5)‐(di)halogenocytisines/cytisine and their pesticidal activities against Mythimna separata Walker, Tetranychus cinnabarinus Boisduval, and Sitobion avenae Fabricius

“…Therefore, the development of new potential pesticides to effectively and selectively control insect pests is very urgent. The discovery and development of potential alternatives derived from natural products has received much attention …”

Dereplication of podophyllotoxin and related cytotoxic lignans in Hyptis verticillata by ultra‐high‐performance liquid chromatography tandem mass spectrometry

“…Podophyllotoxin ( 1 ) and related lignans are isolated from the rhizomes of Podophyllum species (Berberidaceae) and have anticancer properties due to their strong cytotoxic activity, stopping cell division by binding to β ‐tubulin and blocking microtubule assembly. The semi‐synthetic derivatives etoposide, teniposide, and etoposide fosphate (etopophos), which are manufactured from podophyllotoxin, are excellent clinically useful antitumor agents for the treatment of small‐cell lung cancer, testicular carcinoma, lymphomas, nonlymphocytic leukemia, and multiform glioblastoma, usually in combination therapies with other anticancer drugs, due to their potent topoisomerase II inhibitory activity with lower side effects and toxicity than podophyllotoxin . Podophyllum resin (10–25%) in compound benzoin tincture is the standard therapy for the topical treatment of external anogenital warts ( Condyloma acuminata) caused by the human papilloma virus .…”