Design, Synthesis And SAR Studies Of Hybrids Of Lamellarin D And Combretastatin A4

The lamdellarins were firstly isolated from a prosobranch mollus Lamellaria sp.. They belong to a group of over 43 natural pyrrole alkaloids which show interesting anticancer activities.Due to their multidrug resistance(MDR)reversal in some cancer cell lines,the development of a total synthesis and structure modifications in order to create drug candidates for treatment of some forms of cancer have become larger.From this consideration and using the research on another product called Combrestastin A4,which possesses a high anti-mitotic activity,we have decided to aim our studies on a series of compounds which maintain both of the two different mechanisms based on the cytotoxicity and anti-mitotic agents.We have designed and synthesized a new kind of hybrids named 1,2-bis-substitutedphenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline compounds.They combine the structural elements of Lamellarin D and Combretastatin A4 together.We have adopted a simple synthesis strategy involving two components:substituted 1-benzyl-3,4-dihydroisoquinoline and substitutedα-bromoketone.Substituted 1-benzyl-3,4-dihydroisoquinolines were synthesized from substituted phenylacetic acid and substituted phenylethanamine,these two latters were synthesized from substituted benzaldehyde.And substitutedα-bromoketones were made with the bromination of the substituted acetophenones.We have totally synthesized 28 final products,and 26 of them are new compounds. We confirmed our final products with IR,NMR and MS analysis.The measurements in vitro of growth inhibition towards human tumor cell lines, K562 and A549,showed that nearly half of the final products had an activity in different concentrations.However,some of the 1,2-bis-substitutedphenyl-5,6-dihydropyrrolo[2,1-a] isoquinoline compounds,which contain more hydroxyl groups,had higher activities. Moreover,the ones which contain C-8-methyl ether,C-13,14,15-trimethyl ether,and C-20-hydroxyl groups also maintained good cytotoxic activities.Further research on the structure and activity relationships and modifications of 1,2-bis-substitutedphenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline compounds could promote the discovery of a series of better anti-tumor drug candidates.