Attempted Diels-Alder Reactions on Vindoline Derivatives

The Diels-Alder reaction of vindoline and methyl vinyl ketone resulted in a Friedel-Crafts reaction product. In the reaction between the ortho-quinone derivative of vindoline and N-phenylmaleimide, two anomalous products were obtained, a vindoline dimer, and a condensed vindoline derivative

Synthesis, Fluorescence and NMR Spectroscopic Studies of a Novel Phosphinoxido-18-crown-6 Ether Containing an Anthracene Fluorophore Unit

The synthesis of the (R,R) and (S,S) enantiomers of a new enantiopure monophospha-18-crown-6 ether (1), which contains an anthracene fluorophore unit and methyl groups at its stereogenic centers, was accomplished. The structure of one enantiomer ((S,S)-1) was studied using one-dimensional (1H, 13C{1H}, and 31P{1H}) and two-dimensional NMR spectra. Because (R,R)-1 and (S,S)-1 can act as new fluorescent chemosensors, we examined their enantiomeric differentiation abilities toward the enantiomers of protonated chiral primary amines and amino acid esters (PEA, 1-NEA, PGME, PAME) using UV-Vis and fluorescence spectroscopies. These monophospha-crown ethers showed moderate enantiomeric discrimination abilities

The effect of conjugation on antitumor activity of vindoline derivatives with octaarginine, a cell-penetrating peptide

Some Vinca alkaloids (e.g. vinblastine, vincristine) have been widely used as antitumor drugs for a long time. Unfortunately, vindoline, a main alkaloid component of Catharanthus roseus (L.) G. Don, itself, has no antitumor activity. In our novel research program we have prepared and identified new vindoline derivatives with moderate cytostatic activity. Here we describe the effect of conjugation of vindoline derivative with oligoarginine (tetra-, hexa- or octapeptides) cell-penetrating peptides on the cytostatic activity in vitro and in vivo. Br-Vindoline-(L)-Trp-OH attached to the N-terminus of octaarginine was the most effective compound in vitro on HL-60 cell line. Analysis of the in vitro activity of two isomer conjugates (Br-vindoline-(L)-Trp-Arg8 and Br-vindoline-(D)-Trp-Arg8 suggest the covalent attachment of the vindoline derivatives to octaarginine increased the antitumor activity significantly against P388 and C26 tumour cells in vitro. The cytostatic effect was dependent on the presence and configuration of Trp in the conjugate as well as on the cell line studied. The configuration of Trp notably influenced of the activity on C26 and P388 cells: conjugate with (L)-Trp was more active than conjugate with the (D)-isomer. In contrast conjugates had very similar effect on both the HL-60 and MDA-MB-231 cells. In preliminary experiments conjugate Br-vindoline-(L)-Trp-Arg8 exhibited some inhibitory effect on the tumor growth in P388 mouse leukemia tumor-bearing mice. Our results indicate that the conjugation of modified vindoline could result in an effective compound even with in vivo antitumor activity

Optimization and a Kinetic Study on the Acidic Hydrolysis of Dialkyl α-Hydroxybenzylphosphonates

The two-step acidic hydrolysis of α-hydroxybenzylphosphonates and a few related derivatives was monitored in order to determine the kinetics and to map the reactivity of the differently substituted phosphonates in hydrolysis. Electron-withdrawing substituents increased the rate, while electron-releasing ones slowed down the reaction. Both hydrolysis steps were characterized by pseudo-first-order rate constants. The fission of the second P-O-C bond was found to be the rate-determining step

Two step acidic hydrolysis of dialkyl arylphosphonates

The HCl-catalyzed hydrolysis of dialkyl arylphosphonates monitored by 31P NMR spectroscopy has revealed two consecutive steps characterized by pseudo first order rate constants k1 and k2. A reactivity order for the two steps and for the overall two step hydrolysis has been derived depending on the alkoxy and aryl substituents. Besides the AAc2 mechanism, the AAl1 route has been substantiated for the PriO substituent

Novel Ring Systems: Spiro[Cycloalkane] Derivatives of Triazolo- and Tetrazolo-Pyridazines

In orderto synthesize new pyridazine derivatives anellated with different nitrogen heterocyclic moieties, spiro[cycloalkane]pyridazinones were transformed into the corresponding thioxo derivatives via a reaction with phosphorus pentasulfide. The reaction of the formed 2,3-diazaspiro[5.5] undec-3-ene-1-thiones with hydrazine provided the corresponding 1-hydrazono-2,3-diazaspiro[5.5] undec-3-ene, whose diazotization led to the desired spiro[cyclohexane-1,8′-tetrazolo[1,5-b]pyridazines. The reaction of dihydropyridazinethiones with benzhydrazide afforded the corresponding 7H-spiro[[1,2,4]triazolo[4,3-b]pyridazin-8,1′-cyclohexanes]. As a result of our work, seven new pyridazinethione intermediates were prepared, which served as starting materials for the synthesis of two kinds of new ring systems: tetrazolo-pyridazines and triazolo-pyridazines. The six new annulated derivatives were characterized by physicochemical parameters. The new N-heterocycles are valuable members of the large family of pyridazines