Piotr Cmoch

Synthesis of lupane-type saponins bearing mannosyl and 3,6-branched trimannosyl residues and their evaluation as anticancer agents

The saponins modified with mono- or trimannosyl residues can provide a convenient means of delivering drugs to certain human cells via interactions with mannose receptors. In the study reported therein, we developed a convenient approach for the synthesis of 3-O-mannoside and branched trimannoside derivatives of the saponin lupeol and of C-28 acyl esters of 3-O-acetyl-betulinic acid bearing the same mannosyl entities. Lupeol and 3-O-acetyl-betulinic acid were mannosylated with tetra-O-benzoyl- or tetra-O-acetyl-alpha-D-mannopyranosyl trichloroacetimidates. De-esterification followed by regioselective dimannosylation of the unprotected monosaccharide derivatives with 2equiv of tetra-O-benzoyl-alpha-D-mannopyranosyl trichloroacetimidate selectively yielded O-3,O-6-linked trimannosides. The cytotoxic activity of selected lupane-type saponins (derivatives of lupeol, betulinic acid, and betulin) toward normal human fibroblasts and various cancer cell lines was also compared.

Dynamic Formation of Hybrid Peptidic Capsules by Chiral Self‐Sorting and Self‐Assembly

Owing to their versatility and biocompatibility, peptide-based self-assembled structures constitute valuable targets for complex functional designs. It is now shown that artificial capsules based on β-barrel binding motifs can be obtained by means of dynamic covalent chemistry (DCC) and self-assembly. Short peptides (up to tetrapeptides) are reversibly attached to resorcinarene scaffolds. Peptidic capsules are thus selectively formed in either a heterochiral or a homochiral way by simultaneous and spontaneous processes, involving chiral sorting, tautomerization, diastereoselective induction of inherent chirality, and chiral self-assembly. Self-assembly is shown to direct the regioselectivity of reversible chemical reactions. It is also responsible for shifting the tautomeric equilibrium for one of the homochiral capsules. Two different tautomers (keto-enamine hemisphere and enol-imine hemisphere) are observed in this capsule, allowing the structure to adapt for self-assembly.

The tetrazole–azide tautomerism of some nitrotetrazolo [1,5-a]pyridines studied by NMR, IR spectroscopy and molecular orbital calculations

Abstract The 6-nitro- and 8-nitro- groups in the tetrazolo[1,5- a ]pyridine molecule exhibit completely different influences on the tetrazole–azide equilibrium. Introduction of the methyl-, nitro-, azido groups or a bromine atom in positions 5, 6, 7 or 8 of the nitrotetrazolopyridine produce changes in the equilibrium constants. Based on the IR spectra taken in the solid state, the tetrazole structure was assigned for almost all the compounds studied. Only one of them, 2,6-diazido-3-nitropyridine, exists in the diazido-form in the solid. The 1 H, 13 C, 15 N, and 17 O NMR spectral parameters (coupling constants, chemical shifts) as well as ab initio molecular orbital calculations were used to describe the tetrazole–azide tautomerism in solutions. The differences in the NMR parameters between the neutral compound (6,8-dinitrotetrazolo[1,5- a ]pyridine) and its σ-adducts are also included as data for distinguishing between both molecules.

NMR Studies of the Equilibria Produced by 6‐ and 8‐Substituted Tetrazolo[1,5‐a]pyridines

1H, 13C and 15N NMR data are reported for nine tetrazoles. Five of these compounds are found to exhibit valence tautomeric equilibrium between the tetrazole and azide forms. The position of this equilibrium at 298 K is found to be dependent on the solvent and the position and nature of the substituent. More polar solvents favour the tetrazole form. Protonation studies on the two forms using TFA as a solvent are reported. The favoured site of protonation is found to be N‐4 for the azide form and N‐1 for the tetrazole form.

1H,13C and15N NMR and IR studies of halogen-substituted tetrazolo[1,5-a]pyridines

The tetrazole–azide tautomerization of some halogen-substituted tetrazolo[1,5-a]pyridines was examined by IR spectroscopy at ambient temperature and by 1H, 13C and 15N NMR spectroscopy at various temperatures. The tetrazolopyridines can exhibit equilibrium between the azide and the tetrazole forms. For some of them slow exchange occurs on the NMR time-scale, such that it is possible to estimate equilibrium constants. The position and nature of the substituent in the pyridine ring result in stabilization or destabilization of the tetrazole form and exert a strong influence on the values found for the equilibrium constants. A saturation transfer experiment was carried out for 5-bromotetrazolo[1,5-a]pyridine and the rate constants were estimated. Moreover, based on the vant Hoff equation, the enthalpy ΔH° and entropy ΔS° for the tautomerization were calculated. Ab initio calculated energies and charge distribution are in good agreement with differences observed in the tetrazole–azide equilibrium constants. Copyright

Synthesis and biological evaluation of new amino acid and dipeptide derivatives of neocryptolepine as anticancer agents.

The syntheses of neocryptolepine derivatives containing an amino acid or a dipeptide at the C-9 position and their evaluation for antitumor activity in vitro and in vivo are reported. To establish the influence of an amino acid or a peptide on the physicochemical properties of 5H-indolo[2,3-b]quinoline (DiMIQ), lipophilic and hemolytic properties were investigated. Most of the compounds displayed a high antiproliferative activity in vitro and strongly inhibited growth of tumor in mice compared to cyclophosphamide. The attachment of the hydrophilic amino acid or the peptide to the hydrophobic DiMIQ increased its hydrophilic properties and decreased its hemolytic activity. The glycylglycine conjugate (7a) was the most promising derivative. It strongly inhibited the growth of the tumor in mice (at dose 50 mg kg(-1) day(-1) it inhibited the tumor growth by 46-63% on days 11-16 and by 29-43% on days 18-23) and significantly decreased hemolytic activity and lowered the in vivo toxicity compared to DiMIQ.

Synthesis and in vitro antiproliferative activity of 5-alkyl-12(H)-quino[3,4-b] [1,4]benzothiazinium salts.

A novel method of synthesizing 1,4-thiazine ring has led to the series of 5-alkyl-12(H)-quino[3,4-b][1,4]benzothiazinium salts. The derivatives containing a butyl or decyl substituents on the quinoline nitrogen atom were obtained by alkylation of 12(H)-quino[3,4-b][1,4]benzothiazine with alkyl bromides. Antiproliferative activity in vitro of the compounds (3) was assessed using two cancer cell lines (Hct116 and LLC) and doxorubicin as a reference. Most of the studied phenothiazine derivatives showed activity against both cell lines investigated (2.2-19.6 μg/mL concentration range). A structure-activity relationship was established. Only the compounds with substituents in the 11-position of the quinobenzothiazine ring did not exhibit activity against either cell line.

Mechanochemical Encapsulation of Fullerenes in Peptidic Containers Prepared by Dynamic Chiral Self‐Sorting and Self‐Assembly

Molecular capsules composed of amino acid or peptide derivatives connected to resorcin[4]arene scaffolds through acylhydrazone linkers have been synthesized using dynamic covalent chemistry (DCC) and hydrogen-bond-based self-assembly. The dynamic character of the linkers and the preference of the peptides towards self-assembly into β-barrel-type motifs lead to the spontaneous amplification of formation of homochiral capsules from mixtures of different substrates. The capsules have cavities of around 800u2005Å(3) and exhibit good kinetic stability. Although they retain their dynamic character, which allows processes such as chiral self-sorting and chiral self-assembly to operate with high fidelity, guest complexation is hindered in solution. However, the quantitative complexation of even very large guests, such as fullerene C60 or C70 , is possible through the utilization of reversible covalent bonds or the application of mechanochemical methods. The NMR spectra show the influence of the chiral environment on the symmetry of the fullerene molecules, which results in the differentiation of diastereotopic carbon atoms for C70 , and the X-ray structures provide unique information on the modes of peptide-fullerene interactions.

Inherently Chiral Iminoresorcinarenes through Regioselective Unidirectional Tautomerization

Tetraformylresorcin[4]arene is obtained in 48% yield via a chromatography-free Duff reaction. The formylated resorcinarene reacts easily with primary aliphatic and aromatic amines. The resulting imines exist exclusively in keto-enamine forms. Owing to a system of intramolecular hydrogen bonds, the reaction selectively leads to regioisomers with C4 symmetry. They possess an inherent chirality due to a propeller-like skeleton. For chiral amines, inherently chiral diastereoisomers are observed.

1H,13C and15N NMR study of some triazolo- and tetrazolopyridazines and thioxotriazolopyridines

1H, 13C and 15N NMR data are reported for nine azoloazines. From the results obtained it is found that the 15N chemical shifts are particularly well placed to provide reliable data on both the structures of the compounds studied and on their potential to undergo valence and prototropic tautomerism. Of particular note is the high sensitivity of the 15N chemical shifts to changes in the nitrogen electronic environment. In the present work up to seven inequivalent nitrogen atoms may occur in a given molecule and they are readily distinguishable by means of their different 15N chemical shifts. Some ab initio calculated molecular properties (13C and 15N shieldings, partial charges and total SCF energies) were used in the confirmation of the NMR signal assignments, in the prediction of the protonation site and also in the estimation of the most stable tautomers of the compounds studied. Copyright