László Hazai

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 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.

Synthesis of Spiro-substituted Benzo[c]azepinones

Benzo[c]azepinones spiro-substituted by cyclohexanone, cyclohexenone and cyclohexadienone rings were synthesized from 2-tetralone via simple and convenient reaction steps.

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.

3(2H)-Isoquinolinones and Their Saturated Derivatives

Publisher Summary This chapter focuses on the 3(2H)-Isoquinolinones and their saturated derivatives. The name 3(2H)-isoquinolinones is used for the lactam structure to emphasize the connection with derivatives saturated in the hetero ring or in the aromatic ring of the isoquinolinone skeleton or both. One of the most widespread methods of synthesizing 3(2H)-isoquinolinones is the cyclization of esters of o-acyl-phenylacetic acids with appropriate amines. 1, 4-Dihydro-3(2H)-isoquinolinones are structural isomers of the well-known dihydrocarbostyril and dihydroisocarbostyril nitrogen heterocycles. The chapter discusses 5, 6, 7,8-Tetrahydro-3(2H)-isoquinolinones. Several derivatives of the unsaturated and saturated lactams mentioned in the chapter have been submitted to pharmacological investigations, and various biological activities were found. An attempt is made to enumerate some derivatives together with their biological properties. Such compounds are shown in the lactam structure.

Hydrogenation of 3(2H)-isoquinolinones and the stereochemistry of the products

Abstract A new route of preparing 1,4-dihydro-3(2 H )-isoquinolinones and 5,6,7,8-tetrahydrolsoquinolinones was developed by the hydrogenation of 3(2 H )-isoquinolinones. The 1,4-dihydro compounds 1 - 8 , were also prepared by synthesis, when the cis - trans ratio significantly differed from that of the products obtained by hydrogenation. Relative configurations and site of conformational equilibria were established by n.O.e. difference n.m.r. spectroscopy. Compounds 2 , 4 , 5 and 6 had practically one main conformation, whereas 1 , 3 , and 7 occurred as two boat conformers in equilibrium. Complete 1H and 13C signal assignments were achieved by different 2D homo- and heteronuclear correlation measurements.

Synthesis of vinca alkaloids and related compounds 103. Recognition of an unexpected reaction and its application in building the aspidospermane skeleton. simple synthesis of 15β-hydroxyvincadifformine

Reaction of tryptamine derivative (2b) and acetate ester (11) built up from 2-(chloromethylene)butanal (4) resulted in enamino ketone (14). Dehydration of 14 and subsequent intramolecular [4+2] cycloaddition led to 15-oxovincadifformine (15). Regio- and stereoselective reduction of the latter molecule supplied 15β-hydroxyvincadifformine (1).

Synthesis of vinca alkaloids and related compounds. part 109. An intramolecular [4+2] cycloaddition mediated biomimetic synthesis of (±)-iboxyphylline

The pentacyclic alkaloid 1 could be synthesized by an intramolecular [4+2] cycloaddition reaction of intermediate 11, which had been obtained from tryptamine derivative 4 and aldehyde 5. After full epimerization of 13 the cyclization reaction furnished a mixture of 14a and 14b. Separation of the stereoisomers 14a and 14b and subsequent reduction with LiA1H 4 resulted in (±)-iboxyphylline (14a -> 1) and its epimer, (±)-20-epiiboxyphylline (14b -> 15).

Seven-membered ring formation through Grewe-cyclization

Abstract The first example of seven-membered ring formation using Grewe-cyclization of cyclohexene derivatives ( 3b and c ) yielding spiro-substituted benzo[ c ]azepines ( 9b and c ) is presented.

Biomimetic synthesis and HPLC-ECD analysis of the isomers of dracocephins A and B

Starting from racemic naringenin ((±)-1), a mixture of dracocephin A stereoisomers 6-(2”-pyrrolidinone-5”-yl)naringenin (±)-2a–d and its regioisomer, dracocephin B 8-(2”-pyrrolidinone-5”-yl)naringenin (±)-3a–d originally isolated from Dracocephalum rupestre, have been synthesized in a one-pot reaction. The separation of 2a–d and 3a–d was achieved by preparative HPLC. The four stereoisomers of each natural product were separated by analytical chiral HPLC and their absolute configuration was studied by the combination of HPLC–ECD measurements and TDDFT–ECD calculations. The synthesized flavonoid alkaloids were further characterized by physicochemical and in vitro pharmacological studies.