Bispidine Platform as a Tool for Studying Amide Configuration Stability.

In this work, the solution conformations of seventeen 3,7-diacyl bispidines were studied by means of NMR spectroscopy including VT NMR experiments. The acyl groups included alkyl, alkenyl, aryl, hetaryl, and ferrocene moieties. The presence of syn/anti-isomers and their ratios were estimated, and some reasons explaining experimental facts were formulated. In particular, all aliphatic and heterocyclic units in the acylic R(CO) fragments led to an increased content of the syn-form in DMSO-d6 solutions. In contrast, only the anti-form was detected in DMSO-d6 and CDCl3 in the case when R = Ph, ferrocenyl, (R)-myrtenyl. In the case of a chiral compound derived from the natural terpene myrtene, a new dynamic process was found in addition to the expected inversion around the amide N-C(O) bond. Here, rotation around the CO-C=C bond in the acylic R fragment was detected, and its energy was estimated. For this compound, ΔG for amide N-C(O) inversion was found to be equal to 15.0 ± 0.2 kcal/mol, and for the rotation around the N(CO)-C2' bond, it was equal to 15.6 ± 0.3 kcal/mol. NMR analysis of the chiral bispidine-based bis-amide was conducted for the first time. Two X-ray structures are reported. For the first time, the unique syn-form was found in the crystal of an acyclic bispidine-based bis-amide. Quantum chemical calculations revealed the unexpected mechanism for amide bond inversion. It was found that the reaction does not proceed as direct N-C(O) bond inversion in the double-chair (CC) conformation but rather requires the conformational transformation into the chair-boat (CB) form first. The amide bond inversion in the latter requires less energy than in the CC form.

Novel Bispidine-Monoterpene Conjugates-Synthesis and Application as Ligands for the Catalytic Ethylation of Chalcones.

A number of new chiral bispidines containing monoterpenoid fragments have been obtained. The bispidines were studied as ligands for Ni-catalyzed addition of diethylzinc to chalcones. The conditions for chromatographic analysis by HPLC-UV were developed, in which the peaks of the enantiomers of all synthesized chiral products were separated, which made it possible to determine the enantiomeric excess of the resulting mixture. It was demonstrated that bispidine-monoterpenoid conjugates can be used as the ligands for diethylzinc addition to chalcone C=C double bond but not as inducers of chirality. Besides products of ethylation, formation of products of formal hydrogenation of the chalcone C=C double bond was observed in all cases. Note, that this formation of hydrogenation products in significant amounts in the presence of such catalytic systems was found for the first time. A tentative scheme explaining the formation of all products was proposed.

Design, Synthesis, and Molecular Docking Study of New Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors Combining Resin Acids and Adamantane Moieties.

In this paper, a series of novel abietyl and dehydroabietyl ureas, thioureas, amides, and thioamides bearing adamantane moieties were designed, synthesized, and evaluated for their inhibitory activities against tyrosil-DNA-phosphodiesterase 1 (TDP1). The synthesized compounds were able to inhibit TDP1 at micromolar concentrations (0.19-2.3 µM) and demonstrated low cytotoxicity in the T98G glioma cell line. The effect of the terpene fragment, the linker structure, and the adamantane residue on the biological properties of the new compounds was investigated. Based on molecular docking results, we suppose that adamantane derivatives of resin acids bind to the TDP1 covalent intermediate, forming a hydrogen bond with Ser463 and hydrophobic contacts with the Phe259 and Trp590 residues and the oligonucleotide fragment of the substrate.

Aminoadamantanes containing monoterpene-derived fragments as potent tyrosyl-DNA phosphodiesterase 1 inhibitors.

The ability of a number of nitrogen-containing compounds that simultaneously carry the adamantane and monoterpene moieties to inhibit Tdp1, an important enzyme of the DNA repair system, is studied. Inhibition of this enzyme has the potential to overcome chemotherapeutic resistance of some tumor types. Compound (+)-3c synthesized from 1-aminoadamantane and (+)-myrtenal, and compound 4a produced from 2-aminoadamantane and citronellal were found to be most potent as they inhibited Tdp1 with IC50 values of 6 and 3.5 µM, respectively. These compounds proved to have low cytotoxicity in colon HCT-116 and lung A-549 human tumor cell lines (CC50 > 50 µM). It was demonstrated that compound 4a at 10 µM enhanced cytotoxicity of topotecan, a topoisomerase 1 poison in clinical use, against HCT-116 more than fivefold and to a lesser extent of 1.5 increase in potency for A-549.

Anti-influenza activity of diazaadamantanes combined with monoterpene moieties.

The antiviral activity of several diaza-adamantanes containing monoterpenoid moieties against a rimantadine-resistant strain of the influenza A/Puerto Rico/8/34 (H1N1) virus was studied. Hetero-adamantanes containing monoterpene moieties at the aminal position of the heterocycle were found to exhibit lower activity compared to compounds with a diaza-adamantane fragment and a monoterpene moiety linked via an amino group at the 6-position of the hetero-adamantane ring. The highest selectivity index (a ratio of the 50% cytotoxic concentration to the 50% inhibitory concentration) out of 30 was observed for compound 8d, which contains a citronellal monoterpenoid moiety. Diaza-adamantane 8d was superior to its adamantane-containing analog 5 both in its anti-influenza activity and selectivity. Furthermore, 8d has more balanced physicochemical properties than 5, making the former a more promising drug candidate. Modelling these compounds against an influenza virus M2 ion channel predicted plausible binding modes to both the wild-type and the mutant (S31N).

Synthesis and Analgesic Activity of Amines Combining Diazaadamantane and Monoterpene Fragments.

BACKGROUND: It was found earlier that compounds combining diazaadamantane and monoterpene moieties possessed promising analgesic activity along with low acute toxicity and the lack of ulcerogenic activity. OBJECTIVE: In this paper, new structural analogues of the most active compounds were synthesized and evaluated for their analgesic activity. METHODS: Their structures were confirmed by various analytical methods, such as 1H and 13C NMR, HRMS. All of them were evaluated for analgesic activity at a dose of 20 mg/kg or less using acetic acid-induced writhing test and hot plate test. RESULTS: Some compounds showed analgesic activity in acetic acid-induced writhing test. One of the synthesized compounds demonstrated high analgesic activity in both tests with 46% effect in acetic acid-induced writhing test and 89% effect in hot plate test. Both structural fragments of this compound did not possess any analgesic effect at a dose of 20 mg/kg. CONCLUSION: Structure-activity relationships indicated that the most active compound combines fragments of (-)-myrtenal and 6-amino-5,7-dimethyl-1,3-diazaadamantane. Both parts of the molecule are important for demonstrating analgesic activity.

Compounds Combining Aminoadamantane and Monoterpene Moieties: Cytotoxicity and Mutagenic Effects.

A series of secondary amines combining monoterpenoid and aminoadamantane moieties have been synthesized. Their cytotoxic activity against human cancer cells CEM-13, MT-4, and U-937 has been studied for the first time. Most of the obtained compounds exhibited a significant cytotoxic activity with the median cytotoxic dose (CTD50) ranging from 6 to 84 µM. The most promising results were obtained for compound 2b which was synthesized from 1-aminoadamantane and (-)-myrtenal and revealed a high activity against all tumor lines used (CTD50 = 12 ÷ 21 µM) along with low toxicity with respect to MDCK cells (CTD50 = 1500 µM). The synthesized amines do not exert the genotoxic effect on cells of the biosensor strain based on recombinant E. coli cells bearing the pRAC-gfp plasmid.