Introduction

  Harmine, the most representative naturally occurring β-carboline alkaloid, was originally isolated from the seeds of Peganum multisectum Maxim, a medicinal plant indigenous to western China such as Xinjiang. Recent literatures and our preliminary investigation demonstrated that the compounds with β-carboline nucleus had remarkable antitumor activities, together with potential neurotoxicity. In order to search for novel leading compounds which have better antitumor activity and less neurotoxicity, 32 series β-carboline derivatives have been designed and synthesized on the basis of harmine chemical structure using computer-aided drug design (CADD) method with the starting materials harmine and L-tryptophan. Five central sites on the β-carboline ring were modified by different substituent and about 500 β-carboline derivatives were synthesized. Cytotoxic activities in vitro of these compounds were investigated. Furthermore, acute toxicities and antitumor activities of the selected β-carboline derivatives in mice were also evaluated. Two compounds with the tumor inhibition rate over 60% against mice bearing Lewis lung cancer and Sarcoma 180 were acquired.

   

Peganum multisectum Maxim              HepG2 treated with β-carboline

  Some β-carboline derivatives were selected on the basis of the above results and their antitumor molecular mechanisms were investigated by photocleavage assays, DNA binding assays, Topoisomerase inhibition assays and Flow Cytometry (FCM) assays. The ability of photocleavage DNA, intercalation DNA and inhibition Topoisomerase was confirmed. Apoptosis induced by β-carboline derivatives was also validated.

          
Cell apoptosis induced by β-carboline        3D-QSAR model of β-carboline