The design, synthesis, and biological evaluation of dimeric β-carbolines based on the structure of neokauluamine and the study of manzamine A dimerization toward neokauluamine

Neokauluamine, a naturally occurring dimeric β-carboline alkaloid, was isolated from an Indo-Pacific sponge (family Petrosiidae, order Haplsclerida) by Hamann et.al. in 2001. Neokauluamine exhibited improved antimarial activity in vitro and in vivo relative to currently available drugs artemisinin and chloroquine. Moreover, neokauluamine showed potent cytotoxicity against many types of human cancers including lung, colon and cervical cancers. Bases on the structure of neokauluamine, we designed, synthesized and evaluated simple dimeric β-carbolines as lead structures for the development of biologically active compounds. Interestingly, the synthesized dimeric β-carbolines exhibited antimicrobial activity and cytotoxicity against melanoma and lung cancer cell lines comparable to neokauluamine and its monomer, manzamine A. The cellular mechanism by which the dimeric β-carbolines induce cell death in H1299 lung cancer cells was studied and it was found that the β-carboline dimer accumulated in lysosomes and mediated apoptosis by upregulating a pro-apoptotic protein, PUMA (p53 upregulated modulator of apoptosis). The abundance of manzamine A relative to neokauluamine in Nature makes manzamine A an attractive starting material for the synthesis of neokauluamine. Recently, Tsukamoto et.al. discovered a novel manzamine alkaloid, pre-neokauluamine, as the key intermediate in the conversion of manzamine A to neokauluamine. Thus, we designed and synthesized a pre-neokauluamine-based model system to study optimal reaction conditions and selectivity of the key dimerization step

Diphenyl ethers from the cultured lichen mycobiont of Graphis handelii Zahlbr

Purpose: Cultured lichen mycobionts are valuable sources of new natural compounds. Mycobiont of Graphis handelii growing in Vietnam was isolated, cultivated and chemically investigated. The crude extract of this cultured mycobiont showed potent alpha-glucosidase inhibition with an IC50 value of 50 μg/mL. Methods: Multiple chromatographic methods were applied to the extract to isolate compounds. The combination of Nuclear Magnetic Resonance analysis and high-resolution mass spectroscopy determined their chemical structures. Electrophilic bromination/chlorination was applied to obtain new derivatives using NaBr/H2O2 and NaCl/H2O2 reagents. Compounds were evaluated for enzyme inhibitory activities, including alpha-glucosidase inhibition, HIV-1 reverse transcriptase inhibition, SARS-CoV-2 main protease (Mpro) inhibition, anti-inflammatory activity, and cytotoxicity against several cancer cell lines. A molecular docking study for anti-SARS-CoV-2 was conducted to understand the inhibitory mechanism. Results: A new diphenyl ether, handelone (1) and a known compound xylarinic acid A (2) were isolated and elucidated. Four synthetic products 6′-bromohandelone (1a), 2′-bromohandelone (1b), 2′,6′-dibromohandelone (1c), and 2′,6′-dichlorohandelone (1d) were prepared. Compound 1 showed good activity against Mpro with an IC50 value of 5.2 μM but it showed weak or inactive activity in other tests. Other compounds were inactive in all assays. Conclusion: A new compound, handelone (1) was isolated from the cultured mycobiont of Graphis handelii. From these compounds, four new derivatives were prepared. Compound 1 showed good activity against Mpro with an IC50 value of 5.2 μM but it showed weak or inactive activity in other tests. Other compounds were inactive in all assays