Synthesis Of Novel Spin-labeled Podophyllotoxin Derivatives By Isocyanide-based Multicomponent Reactions

Podophyllotoxin is a naturally occurring aryltetralin lignan. Because of its remarkable antiviral, antitumor and insecticidal activity, podophyllotoxin become a popular research object. In the process of exploring structural modifications geared at improving pharmaceutical properties of the podophyllotoxin, many scholars and researchers gradually focused on replacement of the C-4 position of podophyllotoxin and made significant achievements. For example, etoposide (VP-16) and teniposide (VM-26) have been widely used in clinical as anticancer chemotherapy drugs against a variety of cancer. As latent anticancer drugs, NK611, NPF have entered into clinical trials at different stages. Considering that C-4 position modified podophyllotoxin analogues exhibit promising biological activity and applied prospect, epipodophyllotoxin and 4’-demethyl-epipodophyllotoxin were selected as parent compounds and a wide variety of C-4 position podophyllotoxin derivatives were prepared via isocyanide multicomponent reactions (EMCRs). So far, there has been no report on the synthesis of novel podophyllotoxin analogues via isonitrile multicomponent reactions.Firstly, we synthesized isonitrile group at C-4 position of epipodophyllotoxin by using formamide dehydration reaction. Subsequently, we selected appropriate component, including aldehydes/ketones, stable nitroxyl radical acid as acid components and 4-β-NC-epipodophyllotoxin, and further synthesized a series of novel spin-labled epipodophyllotoxin derivatives with a-acyloxy carboxamide group by employing Passerini reactions (P-3CR).Secondly, in order to put forward the previous work, we modified the structures of epipodophyllotoxin and 4’-demethylepipodophyllotoxin at C-4 position by applying the Ugi four component reactions (U-4CR). Then we selected the aldehydes/ketones, amines, stable nitroxide radical acid,4-β-NC-epipodophyllotoxin as reactive components, and synthesized a series of novel spin-labled podophyllotoxin derivatives. Similarly, we selected 4’-demethyl-4-NC-epi podophyllotoxin, which were protected hydroxyl group at C-4’position by TBDMSC1, and synthesized several spin-labeled 4’-demethyl-epipodophyllotoxin derivatives with a-acylaminoamide group by using U-4CR method. The target compounds were tested for their cytotoxicity against four human tumor cell lines (A549, DU-145, KB and KBvin). Among them, compounds 2h-i,21-n and 2p-q displayed significant cytotoxic activity.