Gyorgy Kalaus

Modifications on the Basic Skeletons of Vinblastine and Vincristine

The synthetic investigation of biologically active natural compounds serves two main purposes: (i) the total synthesis of alkaloids and their analogues; (ii) modification of the structures for producing more selective, more effective, or less toxic derivatives. In the chemistry of dimeric Vinca alkaloids enormous efforts have been directed towards synthesizing new derivatives of the antitumor agents vinblastine and vincristine so as to obtain novel compounds with improved therapeutic properties.

Synthesis of vinca alkaloids and related compounds. LIII, A simple synthesis of (±)-3-oxovincadifformine and (±)-3-oxominovine

Starting from ethyl of 3- [5-ethyl-2-oxotetrahydro-1-pyridylethyl]indole-2-carboxylate synthese of the title compounds were achieved via linear reaction sequences

Synthesis of Vinca Alkaloids and Related Compounds, 76.1 Synthesis and Ring Transformations of Compounds with the Aspidospermane- and D-Noraspidospermane Skeleton. A Formal Synthesis Of (±)-12-Demethoxy-N(1)-Acetyl-Cylindrocarine

Abstract Reaction of compound (4) with (5) give a mixture of the isomers (7) and (8) through the intermediate (1). Further conversions led through the oxo- (9), (10) and thioxo (11), (12) derivatives to (±)-19-ethoxycarbonyl-19-demethylvincadifformine (3), and (±)-18-methoxycarbonyl-D(14)-norvincadifformine (13). The preparation of the former compound constitutes the formal synthesis of (±)-12-demethoxy-N(1)-acetylcylindrocarine (2). Oxidative ring transformation of the latter gave (±)-21-methoxycarbony 1-D(18)-norapovincamine (14).

Synthesis and in vitro antitumor effect of vinblastine derivative-oligoarginine conjugates.

Vinblastine is a widely used anticancer drug with undesired side effects. Its conjugation with carrier molecules could be an efficient strategy to reduce these side effects. Besides this, the conjugate could exhibit increased efficiency against resistant cells, e.g., due to the altered internalization pathway. Oligoarginines, as cell-penetrating peptides, can transport covalently attached compounds into different kinds of cells and enhance the efficiency of those compounds. We report here the coupling of vinblastine through its carboxyl group at position 16 with the N-terminal amino function of L-Trp methyl ester. After hydrolysis of the ester group, 17-desacetylvinblastineTrp was conjugated to the N-terminal amino group of oligoarginine via the C-terminal carboxyl group of the Trp moiety in solution. The antitumor effect of conjugates was studied on sensitive and resistant human leukemia (HL-60) cells in vitro. Our data suggest that all conjugates investigated possess an antiproliferative effect against the studied cells. However, the effect was dependent on the number of Arg residues in the conjugates: Arg₈ > Arg₆ ≫ Arg₄. The conjugate with Arg₈ exhibited similar efficicacy as compared with free 17-desacetylvinblastineTrp. The in vitro studies also showed that the tubulin binding ability of vinblastine was essentially preserved even in the octaarginine conjugate. We also observed that two isomers were formed during conjugation. These isomers showed different levels of activity against tubulin polymerization in vitro and in vivo. The 17-desacetylvinblastineTrp-Arg₈-1 isomer conjugate possessed high selectivity against the mitotic spindles. HRMS and NMR data suggest that 17-desacetylvinblastineTrp-Arg₈-1 and 17-desacetylvinblastineTrp-Arg₈-2 are epimers at the tryptophan α carbon atom.

Studies on stereoselective approaches to β-carboline derivatives

Transformation of β-carboline derivatives into optically active entities were studied and the de and ee values of the resulted compounds were detected.

Synthesis of vinca alkaloids and related compounds. Part 101: A new convergent synthetic pathway to build up the aspidospermane skeleton. Simple synthesis of 3-oxovincadifformine and 3-oxominovincine. Attempts to produce 15β-hydroxyvincadifformine

Abstract A molecule with an indole skeleton, containing a latent acrylic ester function—acting as a diene—was produced from Nb-trityl-2-(hydroxy-methyl)-tryptamine and reacted with esters containing an aldehyde or aldehyde-equivalent structural unit, yielding 3-oxo-16,17-dihydro-Δ20-secodin-17-ol type intermediates from which dehydration, followed by [4+2]cycloaddition, furnished 3-oxovincadifformine and 3-oxominovincine. We also wished to apply the method to produce 15β-hydroxyvincadifformine, however, the appearance of a dimeric product with indole skeleton was observed instead of the expected cycloaddition.

Synthesis of vinca alkaloids and related compounds XLII: Transformation of vincamone into vincamines via diazomethane assisted homologization. application of 1h-noe measurements for the configurational as

Abstract The α-oxo-acids 4 and 5 derived from vincamone ( 1 ) were transformed into vicamines 2 , 8 , 10 ,respectively by methylene insertion with diazomethane. Homologisation of 3 and 6 dioxo compounds led to oxirane derivatives 8 , 16 , 11 , 13 , 13 , 18 , respectively. Configuration of the oxiranes was determined by 1H-NOE measurements.

Synthesis of vinca alkaloids and related compounds. Part 102: Simple synthesis and ring transformation of (±)-minovincine. First synthesis of (±)-vincaminine

Abstract A molecule with an indole skeleton, containing a latent acrylic ester function—acting as a diene—readily reacted with benzoic acid (4-bromomethylene-5-oxo)hexyl ester that had been built up from pentane-2,4-dione. Dehydration of the enamine and subsequent [4+2] cycloaddition supplied epimers having the d -secoaspidospermane skeleton. These compounds directly or after epimerization gave (±)-minovincine. Oxidative ring transformation of (±)-minovincine under different conditions led to (±)-16-acetyl-16-deethylapovincamine and (±)-vincaminine.

Synthesis of some aspidosperma and related alkaloids

Publisher Summary This chapter discusses the synthesis of Aspidosperma and related alkaloids. Aspidosperma alkaloids constitute the largest group of indole alkaloids and number well over 220 entities. Dealing with these bases is not only important in order to gain more knowledge about their nature, but some members are also of commercial value. The transformation of aspidospermas such as vincadiflformine to the vincamine, vincamone, and Cavinton is carried out on a large scale. The chapter presents a convergent synthetic pathway that is suitable for the convenient and efficient preparation of a number of compounds having the aspidospermane skeleton. Under this strategy, a compound is prepared from an indole derivative, which on reaction with suitably substituted aldehydes, gives–via the unisolated intermediates (R 1 =Bn)–tetracyclic compounds. Formation of the fifth ring affords the target compounds and as the aldehyde component could be varied, this strategy allows the preparation of many analogous compounds. This enables a convenient synthesis of aspidosperma alkaloids and related compounds.

Synthesis and in vitro antitumor effect of new vindoline derivatives coupled with amino acid esters

10-Bromovindoline and its 14,15-dihydro- and 14,15-cyclopropano derivatives were coupled in the position 16 with (L)- and (D)-tryptophan methyl esters. The tryptophan derivatives of vindoline were synthesized starting from the 16-carboxylic acid hydrazides viathe corresponding azides which were allowed to react with the amino acidesters. The new compounds showed antitumor activity against human leukemia (HL-60) cells in vitro.