The antitumor indole–indoline alkaloids of the evergreen Catharanthus roseus—namely vinblastine and vincristine—are widely used in chemotherapy of cancer. Many efforts were made to synthesize more efficient derivatives with less side-effect. The 14,15-cyclopropane derivative of vinblastine was synthesized successfully by a five-step procedure starting from vindoline. Vincristine, vinorelbine and several derivatives condensed with a cyclopropane ring were synthesized. Various hybrid molecules were prepared by the coupling reaction of vindoline and methyl ester of tryptophan, which were conjugated by carrier peptides of octaarginine. Studying the halogenation reactions of vindoline and catharanthine some fluorine derivatives were obtained which showed promising antitumor activity on various tumor types. The synthesis of the Aspidospermane alkaloid bannucine and 5′-epibannucine were carried out using N-acyliminium intermediates. The same intermediate was also applied in the first synthesis of sessiline. The research group have synthesized of flavonoid alkaloids: dracocephins A and B. Further three flavonoid alkaloids, namely 8-(2”-pyrrolidinon-5′′-yl)quercetin, 6-(2′′-pyrrolidinon-5′′-yl)-(−)- and 8-(2′′-pyrrolidinon-5′′-yl)-(−)-epicatechin were prepared by acid-catalyzed regioselective Mannich reaction starting from the corresponding flavonoid precursor. Vindoline was also coupled to synthetic pharmacophores, such as triphenylphosphine and various N-heterocycles. Some of these hybrid molecules showed significant antitumor activity. Furthermore, 7-OH and 7-NH modified flavonoid derivatives were synthesized by a regioselective alkylation followed by Smiles rearrangement and hydrolysis.
Background: owadays, in course of the drug design and discovery much attention is paid to the physicochemical parameters of a drug candidate, in addition to their biological activity. Disadvantageous physicochemical parameters can hinder the success of a drug candidate. Objective: Lovering et al. introduced the Fsp3 character as a measure of carbon bond saturation, which is related to the physicochemical paramethers of the drug. The pharmaceutical research focuses on the synthesis of compounds with high Fsp3 character. Methods: To improve the physicochemical properties (clogP, solubility, more advantageous ADME profile, etc.) of drug-candidate molecules one possibility is the replacement of all-carbon aromatic systems with bioisoster heteroaromatic moieties, e.g. with one or two nitrogen atom containing systems, such as pyridines and pyridazines, etc. The other option is to increase the Fsp3 character of the drug candidates. Both of these aspects were considered in the design the new spiro[cycloalkanepyridazinones], the synthesis of which is described in the present study. Results: Starting from 2-oxaspiro[4.5]decane-1,3-dione or 2-oxaspiro[4.4]nonane-1,3-dione, the corresponding ketocarboxylic acids were obtained by Friedel-Crafts reaction with anisole or veratrole. The ketocarboxylic acids were treated by hydrazine, methylhydrazine or phenylhydrazine to form the pyridazinone ring. N-Alkylation reaction of the pyridazinones resulted in the formation of further derivatives with high Fsp3 character. Conclusion: A small compound library was obtained incorporating compounds with high Fsp3 characters, which predicts advantageous physico-chemical parameters (LogP, ClogP and TPSA) for potential applications in medicinal chemistry.
An extended compound library of spiro[cycloalkane-pyridazinones] with high Fsp3 character is targeted. There are two possibilities to improve the physicochemical parameters of a drug candidate molecules or building blocks, either to replace the aromatic systems with bioisoster heteroaromatic moieties, e.g. with one or two nitrogen containing ring systems (pyridines, pyridazines, pyrimidines, etc.), or to increase the Fsp3 character of the compounds. Using a new synthetic ap-proach, the Grignard reaction of 2-oxaspiro[4,5]decane-1,3-dione and 2-oxaspiro[4,4]nonane-1,3-dione with p-halophenyl- or p-alkylphenyl-magnesium bromide resulted in the formation of the corresponding 2-oxoethyl-cycloalkanecarboxylic ac-ids, which served as starting materials for the formation of pyridazinone with hydrazine or phenylhydrazine. The pyridazi-nones obtained were alkylated with methyliodide or benzylbromide. 16 Novel 4-tolyl- or 4-halophenyl-2,3-diazaspiro[5.5]undec-3-en-1-one and 4-tolyl- or 4-halopyhenyl-7,8-diazaspiro[4.5]dec-8-en-6-one, and their N-methyl, N-benzyl, and N-phenyl derivatives were synthetized.The physicochemical parameters and the Fsp3 character of the novel compounds obtained were studied. A few of them showed excellent logP and clogP values, but introduction of further phe-nyl group seemed to be disadvantageous
The large originator pharmaceutical companies need more and more new compounds for their molecule banks, because high throughput screening (HTS) is still a widely used method to find new hits in the course of the lead discovery. In the design and synthesis of a new compound library, important points are in focus nowadays: Lipinski’s rule of five (RO5); the high Fsp3 character; the use of bioisosteric heterocycles instead of aromatic rings. With said aim in mind, we have synthesized a small compound library of new spiro[cycloalkane-pyridazinones] with 36 members. The compounds with this new scaffold may be useful in various drug discovery projects.
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.
A biológiailag aktív természetes anyagokkal foglalkozó kutatások három fõ csoportra oszthatók. Az elsõ a szerves anyag izolálása az adott növénybõl, a második a totálszintézis kidolgozása a hatásos szerkezet elõállítására, a harmadik pedig a már meglévõ struktúra módosításával hatékonyabb, szelektívebben kötõdõ, kevésbé mérgezõ származékok szintetizálása.A (-)-vindolin (1) és a (+)-katarantin (2) indolvázas alkaloidok, amelyek összekapcsolódva alkotják a (+)-vinblasztint (3) és a (+)-vinkrisztint (4). A vinkrisztin (4) abban tér el a vinblasztintól (3), hogy a vindolin rész 1-es helyzetében N-metilcsoport helyett N-formilcsoportot tartalmaz (1. ábra). Ezek a vegyületek a Vinca alkaloidok sorába tartoznak, és elõször az 1950-es években izolálták õket a Madagaszkáron õshonos rózsás meténgbõl (Catharantus roseus). Ezek a dimer alkaloidok tumorellenes szerek, amelyek gyógyszerként is forgalomban vannak. A sejtosztódás során inhibitorként hatnak a sejtciklus metafázisában, amelyet a mikrotubulusokhoz kötõdve a mitotikus orsó kialakulását gátolva érnek el. Tumorsejtekben gátolják a DNS-javító mechanizmust, és a DNS-dependens RNS-polimeráz gátlása révén a RNS-szintézist. A rákterápiában leginkább leukémia és limfómák esetén használatosak. ábraMár számos publikáció született a vinblasztin (3) és a vinkrisztin (4) kémiai és biológiai tulajdonságairól, valamint biológiailag hatásos származékaik szintézisérõl. 1,2,3 Kutatómunkánk során új vinblasztin-és vinkrisztin származékok elõállításán túlmenõen célunk volt az õket felépítõ monomerek, a vindolin (1) és katarantin (2) kémiájának alapos tanulmányozása. Kutatócsoportunk ezen a téren elért legfontosabb eredményeirõl 2015-ben részletes összefoglaló cikk is megjelent. 4 Háromtagú gyûrûvel kondenzált származékokKorábban már megfigyelték, hogy a vinblasztin (3) 14,15-ös helyzetû kettõskötését katalitikus hidrogénezéssel telítve a biológiai hatás nagyjából két nagyságrenddel csökken. 5 Tekintettel arra, hogy ez az apró módosítás ezen a hatalmas molekulán ilyen drasztikus változást okoz, arra következtettünk, hogy ennek a telítetlenségnek kulcsszerepe lehet a biológiai hatásban. Mivel ezek a vegyületek alkalmasnak látszanak ebben a pozícióban a ciklopropanálásra, felmerült a kérdés, hogyan a változik a biológiai hatás, ha ezt a kettõskötést az elektronikusan hasonló ciklopropángyûrûvel helyettesítjük. Ezért célul tûztük ki a 14,15-ös helyzetben ciklopropángyûrût tartalmazó vindolinés vinblasztin származékok elõállítását.A ciklopropánváz számos vegyületben, közöttük természetes anyagokban is megtalálható kondenzált és nem kondenzált formában is. 6 Mindamellett a ciklopropángyûrû egyedi szerkezetének köszönhetõen különleges tulajdonsággal rendelkezik. Különbözõ ciklopropán-származékok NMR spektrumaiból arra következtettek, hogy a ciklopropángyûrûben a C-H kötés nagyobb s karakterrel bír, mint más szénhidrogénekben, ezért viszont a C-C kötések nagyobb p karakterrel rendelkeznek. Kiszámolták, hogy ezek a C-C kötések 17% s karakterrel bírnak, ami sp 5 hibridállapotnak felel meg. Ezt t...
After making a new series of spiro[cycloalkane]pyridazinones with high Fsp3 character available, the new target was to synthesize derivatives comprising nitrogen-containing heterocycles, such as triazolo or tetrazolo rings. The corresponding thioxo derivatives (1a,b) seemed to be good starting materials for the synthesis of tetrazolo derivatives. The reaction of the pyridazinethiones (1a,b) with hydrazine surprisingly resulted in Schiff bases (3a,b) deriving from the reaction of hydrazones (2a,b) with acetone.
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