Facial Synthesis and Bioevaluation of Well-Defined OEGylated Betulinic Acid-Cyclodextrin Conjugates for Inhibition of Influenza Infection.

Betulinic acid (BA) and its derivatives exhibit a variety of biological activities, especially their anti-HIV-1 activity, but generally have only modest inhibitory potency against influenza virus. The entry of influenza virus into host cells can be competitively inhibited by multivalent derivatives targeting hemagglutinin. In this study, a series of hexa-, hepta- and octavalent BA derivatives based on α-, ß- and γ-cyclodextrin scaffolds, respectively, with varying lengths of flexible oligo(ethylene glycol) linkers was designed and synthesized using a microwave-assisted copper-catalyzed 1,3-dipolar cycloaddition reaction. The generated BA-cyclodextrin conjugates were tested for their in vitro activity against influenza A/WSN/33 (H1N1) virus and cytotoxicity. Among the tested compounds, 58, 80 and 82 showed slight cytotoxicity to Madin-Darby canine kidney cells with viabilities ranging from 64 to 68% at a high concentration of 100 µM. Four conjugates 51 and 69-71 showed significant inhibitory effects on influenza infection with half maximal inhibitory concentration values of 5.20, 9.82, 7.48 and 7.59 µM, respectively. The structure-activity relationships of multivalent BA-cyclodextrin conjugates were discussed, highlighting that multivalent BA derivatives may be potential antiviral agents against influenza infection.

Synthesis and antiviral activity of maleopimaric and quinopimaric acids' derivatives.

A series of maleopimaric and quinopimaric acids' derivatives modified in the E-ring, at the carbonyl- and carboxyl-groups were synthesized and evaluated for their activity in vitro against respiratory viruses (influenza; rhinovirus; adenovirus; and SARS), papilloma virus, and hepatitis B and C viruses. The antiviral screening of levopimaric acid diene adducts derivatives was carried out with minimal effect on SARS and influenza type B viruses. Excellent antiviral activity of the ozonolysis product of maleopimaric acid and dihydroquinopimaric methyl-(2-methoxycarbonyl)ethylene amide was found toward papilloma virus (HPV-11 strain) with the selectivity index of SI 30 and 20, respectively. Methyl (2-methoxycarbonyl)ethylene-, 1ß-hydroxy-5'-kaprolaktamo- and 4ß-hydroxy-4α,14α-epoxy-13(15)-ene-dihydroquinopimaric acid derivatives have also shown activity against replication of HCV nucleic acid and low toxicity.

Synthesis and anticancer activity of quinopimaric and maleopimaric acids' derivatives.

A series of quinopimaric and maleopimaric acids' derivatives modified in the E-ring, at the carbonyl- and carboxyl-groups were synthesized and their in vitro cytotoxic activity was evaluated at the National Cancer Institute, USA. Methyl esters of dihydroquinopimaric, 1a,4a-dehydroquinopimaric, 2,3-epoxyquinopimaric, 1-ethylenketal-dihydroquinopimaric, 1-ethylenketal-4-hydroxyiminodihydroquinopimaric acids displayed an activity on renal cancer, leukemia, colon cancer and breast cancer cell lines in concentration 10(−5) M. Methyl 1,4-dihydroxyiminodihydroquinopimarate showed both a potent and broad spectrum of cytotoxic activity against NSC lung cancer, colon cancer, breast cancer, renal cancer and leukemia and revealed in vivo antineoplastic activity towards mouse solid transplantable mammary carcinoma Ca755 and colon adenocarcinoma AKATOL. The information about antineoplastic activity of the studied quinopimaric and maleopimaric acids' derivatives will be used for hit to lead optimization in these chemical series.

Synthesis and bioevaluation of water-soluble ß-cyclodextrin-diterpene acid conjugates.

A series of ß-cyclodextrin (ß-CD)-conjugates were prepared by combining three abietane-type diterpene acids with two azide-functionalized ß-CDs via click chemistry, and the antiviral activity against wild-type and omicron SARS-CoV-2 spike pseudovirus as well as the antibacterial activity against Escherichia coli were investigated. All the synthesised conjugates exhibited no significant cytotoxicity to BHK-21-hACE2 cells with cell viability over 80% at concentration of 15 µM. Among the conjugates, the heptavalent ß-CD-dehydroabietic acid conjugate 6b exhibited higher anti-SARS-CoV-2 activity against the omicron variant compared to the other conjugates. This study suggested that the multivalent diterpene acid derivatives may have potential application against coronaviruses as entry inhibitors.

Abietic, maleopimaric and quinopimaric dipeptide Ugi-4CR derivatives and their potency against influenza A and SARS-CoV-2.

A set of 12 abietane diterpene derivatives have been synthesised by the Ugi-four component reaction (Ugi-4CR) and tested for cytotoxicity and activity against influenza virus A/Puerto Rico/8/34 (H1N1) and SARS-CoV-2 pseudovirus. Five dipeptide derivatives demonstrated a selectivity index (SI) higher than 10 and IC50 values from 2 to 32 µM against influenza virus. Compound 11 was found to be a lead with SI of 200, and time-of-addition experiments showed the viral entry into the cell and the binding of the virus to the receptor as a possible target. Compound 7 was the only one showed weak anti-SARS-CoV-2 activity with EC50 value of 80.96 µM. Taken together, our data suggest the potency of diterpene acids-Ugi products as new effective anti-influenza compounds.

Synthesis of New Dihydroquinopimaric Acid Analogs with Nitrile Groups as Apoptosis-Inducing Anticancer Agents.

BACKGROUND: Cyan-containing compounds are of great interest as potential anticancer agents. Terpenoids can severe as a natural matrix for the development of promising derivatives with antitumor activity. METHODS: The 2-cyanoethoxy methyl dihydroquinopimarate derivatives (5-9) were synthesized by the reaction of the intermediates (1-4) with acrylonitrile in the presence of alkali (30% KOH solution) using triethylbenzylammonium chloride. The cytotoxicity evaluation was carried out according to the National Cancer Institute (NCI) Protocol, while apoptosis was studied by flow cytometric analysis of Annexin V and 7-aminoactinomycin D staining and cell cycle was analyzed using the method of propidium iodide staining. RESULTS: Synthesis of new dihydroquinopimaric acid derivatives with nitrile groups was carried out. The obtained cyanoethyl derivatives were converted into tetrazole, amine, oxadiazole and amidoxime analogs. The primary screening for antitumor activity showed the highest cytotoxic potency of the cyanoethyl-substituted compounds. The introduction of cyanoethyl groups at C-1, C-4 and C-1, C-4, C-20 positions of dihydroquinopimaric acid methyl ester provided antiproliferative effect towards the Jurkat, K562, U937, and HeLa tumor cell cultures (CC50=0.045-0.154µM). These nitrile derivatives are effective inducers of tumor cell apoptosis affecting the S and G2 phases of the cell cycle in a dose-dependent manner. CONCLUSION: The cyanoethyl analogs of dihydroquinopimaric acid reported herein are apoptosis inducers and cytotoxic agents. These findings will be useful for the further design of more potent cytotoxic agents based on natural terpenes.

Synthesis of a Novel 1,2,4-Oxadiazole Diterpene from the Oxime of the Methyl Ester of 1ß,13-Epoxydihydroquinopimaric Acid.

Oximation of the dihydroquinopimaric acid O-cyanoethylderivative (2) via the amidoxime 3, and cyclization with trifluoroacetic anhydride resulted in a new 1,2,4-oxadiazole diterpenoid (4).

Synthesis of 5,19-(2,6-Dimethylpyridin-4-yl)-trisnorlupane and Oleanane.

Acetylation of the 3,4-seco-derivatives of betulin, allobetulin and 28-oxyallobetulone gave the 5,19-(2,6-dimethylpyridin-4-yl)-4,23,24,20,29,30-hexanorlupane, and 5-(2,6-dimethylpyridin-4-yl)-4,23,24-trisnor-derivatives of oleanane and ursane.

An efficient oxyfunctionalization of quinopimaric acid derivatives with ozone.

An access to oxyfunctionalized quinopimaric acid derivatives is reported. The ozonolysis of methyl dihydroquinopimarate occurs through 1,2-cycloaddition of ozone to the bridging double bond followed by intermolecular rearrangements and formation of nontrivial 4beta-hydroxy-4alpha,14alpha-epoxy-13(15)-ene derivative 2. The oxidation of methyl furfurilydene dihydroquinopimarate with ozone led to anhydride 5 and unexpected carboxymethyl substituted cyclopentane lactone 6. The structure of compound 6 was confirmed by X-Ray analysis of its methyl ester.