Synthesis Study Of Novel Poly-aaptamine Alkaloids From Sponge

Aaptamine and its natural congeners containing a benzo[de][1.6]naphthyridine framework, collectively known as "aaptamines", are marine alkaloids isolated from Demospongiae sponge. Its diverse chemical structures including dimeric, rearranged and differently functionalized of benzo[de][1.6]naphthyridine skeletons result in significant biological activities involving scavenging free radicals, antitumor, antibacterial, antiviral, anti-inflammatory, enzymatic inhibition, parasitic resistance, alpha adrenaline receptor antagonist et al. For example, aaptosine demonstrated cytotoxic activity against P388 cells(IC50=1.0//g/mL); N4-methylaaptamine were found to inhibit replication of HSV-1 in Vero cells(ECso=2.4 μM); isoaaptamine can inhibit the enzyme of Sortase A in S. aureus Newman strains with IC50 values of 3.7μg/mL; nakijinamines C/E exhibited antifungal activity against Aspergillis niger(MIC=16μg/mL). However, aptamine are mainly isolated from marine sponges with low proportion and high cost of development, which limits its more extensive biological activity studies. Therefore, using synthetic chemistry, the semi-synthesis, total synthesis, and structure modification of the aaptamine alkaloids, promotes significantly the development of aaptamines for approaching the pharmaceutical potential.In this paper, we try to synthesis a novel poly-aaptamine isolated from the marine sponge Aaptos suberitoides collected the South China Sea by our group earlier. The polymers are mainly divided into two types:one kind is C-3 or C-6 mutual coupling, the other is C-3 connected with C-9. The bioactivity study show that poly-aaptamine demonstrated cytotoxic and enzymatic inhibition activity:Suberitine B、 D、F show cytotoxic activity against P388 cells(IC50=1.8,3.5,1.6 μM), Suberitine F also showed cytotoxic activity against K562 cells(IC50=9.3 μM) and C-Met enzyme inhibition activities(IC50=5.4μM). We propose to synthesis this kind of alkaloids by chemical method.The paper is divided into three main parts:The first part summarizes the studies about aaptamine both in isolating and biological activities. We also overview the studies of aaptamine including total synthesis, structure modification and structure-activity relationship.The second part, we aime at compounds Suberitines, Suberitine A and C was synthesized by palladium catalyzed coupling reaction with 8,9,9-trimethoxy-9H-benzo[de][1,6]-naphthyridine as raw material.The third part we studied the chemical total synthesis of monomer aapatamine. DCC-mediated coupling of homoveratrylamine and N-trifluoroacetyl-β-alanine to afforded amide, then cyclizated by Bischler-Napieralski reaction afforded the 3,4-dihydroisoquinoline, after cleavage of the methyl ether groups and trifluoroacetamido moiety, employing an oxidative cyclization with 1% aqueous KOH and potassium peroxodisulfate or air, we get the bisdemethyl(oxy)aaptamine. After selective methylation, we get the monomer aapatamine:demethyl(oxy)aaptamine and 8,9,9-trimethoxy-9H-benzo[de][1,6]-naphthyridine.In conclusion, the present study completed the semi-synthetic studies of polymerized aaptaniine alkaloids with new carbon skeleton exclusive to Xisha sponge of Aaptos suberitoides. A modified Suzuki coupling reaction was used to constructed successfully Suberitine A and C. Furthermore, an explorative total synthesis of the aaptamine monomers was performed, which has been developed well. The research is expected to provide scientific data for the in-depth studies of aaptamine alkaloids, and further supply a meaningful exploration for promoting the development and utilization of marine drugs using semi-synthesis as an important alternative method.