Alkylation of the simple polyphenol model resorcinol with 10-chloroacetamidovindoline resulted in the corresponding O,Odisubstituted derivative containing two elements of the Vinca alkaloid. The in vitro anticancer activity of the hybrid was investigated on the NCI-60 human tumor cell line panel, and the most important value was obtained on UO-31 renal cancer cells (50% growth inhibition GI50 = 0.893 & micro;M).

The Vinca alkaloid vindoline was coupled at position 17 with several trisubstituted phosphine derivatives and their in vitro anticancer activities on 60 human tumor cell lines (NCI60) were investigated. This phosphonium-type ionic side chain is beneficial because it allows therapeutic molecules to pass through the cell membrane. Thus, the candidates coupled to it can exert their activities in the mitochondria. The coupling of vindoline with the trisubstituted phosphines was achieved through flexible or rigid linkers. Instead of the ionic phosphonium structural part, a neutral moiety, namely the triphenylmethyl group, was also added to the side chain, being sterically similar but without a charge and phosphorus atom. In addition, the triphenylphosphine element was also built at position 10 of vindoline. Most of the derivatives showed low micromolar growth inhibition (GI50) values against most cell lines. Among them, conjugate 9e was outstanding: it exhibited nanomolar anticancer activity on the RPMI-8226 leukemia cell line (GI50 = 20.0 nM). Compound 9g elicited cell cycle disturbance and apoptosis on A2780 ovary cancer cells and inhibited their migration at subantiproliferative concentrations. The selectivity of the conjugates was determined by their effects on non-tumor Chinese hamster ovary (CHO) cells in the CellTiter-Glo Luminescent Cell Viability Assay. Compound 9e showed an estimated half-maximal inhibitory concentration (IC50) value of 1.36 µM, suggesting good selectivity on cancer cells. These results open new perspectives of novel phosphonium-based vindoline derivatives as anticancer compounds.

One of the best-known flavonoid chrysin was coupled at position 7 with several trisubstituted phosphine derivatives with a flexible spacer, and their in vitro anticancer activities were investigated on 60 human tumor cell lines (NCI60) and on several gynecological cancer cells. The trisubstituted phosphines contained different substituents on the aromatic ring(s), e.g., methyl and methoxy groups or fluoro atoms. The phosphorus atom was substituted not only with aromatic rings but with cyclohexyl substituents. The ionic phosphonium building block is important because it allows the therapeutic agents to transfer across the cell membrane. Therefore, the pharmacophores linked to it can exert their effects in the mitochondria. Instead of the ionic phosphonium element, a neutral moiety, namely the triphenylmethyl group, was also added to the side chain, being sterically similar but without a charge and phosphorus atom. Most of the hybrids exhibited low micromolar growth inhibition (GI50) values against the majority of the tested cell lines. Notably, conjugate 3f stood out, demonstrating nanomolar antitumor activity against the K-562 leukemia cell line (GI50 = 34 nM). One selected compound (3i) with promising cancer selectivity elicited cell cycle disturbances and inhibited the migration of breast cancer. The tumor-selectivity of 3a and 3f was assessed based on their effects on non-tumor Chinese hamster ovary (CHO) cells using the CellTiter-Glo Luminescent Cell Viability Assay. Given their estimated half-maximal inhibitory concentration (IC50) values on non-tumor CHO cells (2.65 µM and 1.15 µM, respectively), these conjugates demonstrate promising selectivity toward several cancer cell lines. The excellent results obtained may serve as good starting points for further optimization and the design of even more effective flavonoid- and/or phosphonium-based drugs.

Hybrid molecules can be defined as chemical entities with two or more structural domains, namely pharmacophores, having a specific biological effect. In many cases, when at least one of the components is biologically inactive, it is rather correct to call them “derivatives”, despite the fact that in the literature they are often mentioned also as hybrids. We have summarized such types of molecules, in which one of the components is mostly a real pharmacophore, i.e., flavone, which is one of the best-known natural bioactive substances. Structures, synthetic methods, medicinal indications, and more important activity data are presented.

Vinblastine was investigated in the presence of cyclodextrin derivatives on different cancer cells and it was established that the anticancer activity was unchanged. This was the first step of a long procedure resulting in the dosage of vinblastine together with cyclodextrin or its derivatives to improve the adverse effects.

A series of novel vindoline–piperazine conjugates were synthesized by coupling 6 N-substituted piperazine pharmacophores at positions 10 and 17 of Vinca alkaloid monomer vindoline through different types of linkers. The in vitro antiproliferative activity of the 17 new conjugates was investigated on 60 human tumor cell lines (NCI60). Nine compounds presented significant antiproliferative effects. The most potent derivatives showed low micromolar growth inhibition (GI50) values against most of the cell lines. Among them, conjugates containing [4-(trifluoromethyl)benzyl]piperazine (23) and 1-bis(4-fluorophenyl)methyl piperazine (25) in position 17 of vindoline were outstanding. The first one was the most effective on the breast cancer MDA-MB-468 cell line (GI50 = 1.00 μM), while the second one was the most effective on the non-small cell lung cancer cell line HOP-92 (GI50 = 1.35 μM). The CellTiter-Glo Luminescent Cell Viability Assay was performed with conjugates 20, 23, and 25 on non-tumor Chinese hamster ovary (CHO) cells to determine the selectivity of the conjugates for cancer cells. These compounds exhibited promising selectivity with estimated half-maximal inhibitory concentration (IC50) values of 2.54 μM, 10.8 μM, and 6.64 μM, respectively. The obtained results may have an impact on the design of novel vindoline-based anticancer compounds.

In the frame of our diversity-oriented research on multitarget small molecule anticancer agents, utilizing convergent synthetic sequences terminated by Sonogashira coupling reactions, a preliminary selection of representative alkyne-tethered vindoline hybrids was synthesized. The novel hybrids with additional pharmacophoric fragments of well-documented anticancer agents, including FDA-approved tyrosine-kinase inhibitors (imatinib and erlotinib) or ferrocene or chalcone units, were evaluated for their antiproliferative activity on malignant cell lines MDA-MB-231 (triple negative breast cancer), A2780 (ovarian cancer), HeLa (human cervical cancer), and SH-SY5Y (neuroblastoma) as well as on human embryonal lung fibroblast cell line MRC-5, which served as a reference non-malignant cell line for the assessment of the therapeutic window of the tested hybrids. The biological assays identified a trimethoxyphenyl-containing chalcone-vindoline hybrid (36) as a promising lead compound exhibiting submicromolar activity on A2780 cells with a marked therapeutic window.

Hybrid compounds of flavones, namely chrysin and kaempferol, and substituted 1,2,3-triazole derivatives, were synthesized by click reaction of the intermediate O-propargyl derivatives. 4-Fluoro- and 4-nitrobenzyl-1,2,3-triazole-containing hybrid molecules were prepared. The mono- and bis-coupled hybrids were investigated on 60 cell lines of 9 common cancer types (NCI60) in vitro as antitumor agents. Some of them proved to have a significant antiproliferative effect.

Chrysin, a well-known naturally occurring flavonoid having several biological effects including antiproliferative activity, was coupled with different pharmacophore structures. Coupling was carried out with spacers of different lengths and types. Structures selected for hybrid formation were amines, cyclic amino acid esters, and (hetero)aromatic compounds. In addition, vindoline, which is a Vinca alkaloid containing an indole skeleton, was also used. The alkylation of amines in the presence of carbonate base resulted in an interesting carbamate side product formation beside the expected amine. We also present the detailed structure elucidation of the carbamates. The in vitro anticancer activities of the synthesized derivatives were examined against 60 human tumor cell lines in National Cancer Institute (NCI, USA).

Vinca alkaloids used in anticancer therapy are the well-known vinblastine and vincristine as classical antitumor agents. These dimeric molecules consist of two monomers, vindoline and catharanthine, which have no particular activity on their own. The goal in our research work was to obtain derivatives of one of these, vindoline, resulted in molecules with important antiproliferative effect. This type of derivatives were hybrids; vindoline was conjugated with several pharmacophores with and/or without linkers. Pharmacophores were amino acid esters, steroids, triazoles, and flavones. In several cases, the synthesized compounds showed on some cell lines an even better effect than vinblastine.

Vinca alkaloids are well-known microtubule targeting agents, which are used against some types of cancer. Vindoline is one of the monomeric Vinca alkaloids which does not have anti-tumor effect, although its derivatives have serious impact on the field of these indole alkaloids. Chrysin is a secondary plant metabolite, which has broad-spectrum biological activity, among others anticancer activity. Chrysin had shown synergic effect with several antiproliferative compounds (e. g., doxorubicin, cisplatin and ciglitazone), therefore, we attempted the synthesis of a novel vindoline-chrysin hybrid molecule. However, in the first case a diphenylamine structure was isolated. The mechanism of the unexpected reaction was studied, and then the originally targeted hybrid was synthesized by a reverse route coupling. A further hybrid was produced using a different site of the molecule. The antitumor activities were determined against 60 human tumor cell lines (NCI60), where the aimed hybrid showed low micromolar GI(50) values on most of the cell lines.

An extended compound library of spiro[cycloalkane-pyridazinones] with a high Fsp(3) 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 Fsp(3) character of the compounds. Using a new synthetic approach, 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 acids, which served as starting materials for the pyridazinones by reaction with hydrazine or phenylhydrazine. The pyridazinones 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 Fsp(3) character of the novel compounds obtained were studied. A few of them showed excellent logP and clogP values, but the introduction of a further phenyl group seemed to be disadvantageous.

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.

We hereby report the synthesis of six racemic alkaloids isolated from Lilium candidum L. Their common structural feature is a five-membered lactam ring which is, in the case of the flavonoid alkaloid lilaline, attached to the molecule’s aromatic core, while in the case of the other five compounds, it is connected to the nitrogen atom of a pyrrolinone ring by an aminal function. The syntheses of these natural products were achieved via Mannich-type alkylations through cyclic N-acyliminium ions as intermediates. Besides the synthesis, the so far unexplored stereochemistry of these natural products was determined by a combination of NMR-based proton–proton distance measurements and theoretical conformational analyses carried out at the DFT level.

The chemistry and pharmacology of the important Vinca alkaloids such as vinblastine and vincristine used in anticancer therapy are still investigated widely. Several new derivatives, e.g., vinflunine, vinorelbine, and vindesine, have been synthesized and become successful medicines in anti-cancer therapy. In 2012, we published a paper that reviewed the Vinca derivatives. Nevertheless, the interest in the preparation of new modified structures is not decreasing either in recent years. In this review, the vinblastine-type molecules with several substituents, e.g., amide, nitrile, hydrazide, substituted side chains, etc. in different positions of catharanthine and/or vindoline cores are presented. An important part of the review is the derivatization of the monomer alkaloid vindoline, which possesses no antitumor effect. Additionally, new hybrid molecules of these alkaloids are also discussed in this mini-review.

Chrysin is a naturally occurring flavonoid with mild anticancer activity. In this paper we report the synthesis of new chrysin derivatives alkylated with N-phenylchloroacetamides in position 7. A novel method was developed for the preparation of 7-aminochrysin derivatives via the Smiles rearrangement, resulting in diphenylamine-type compounds. In silico studies of the Smiles rearrangement were performed. We also present the in vitro antiproliferative activity of the synthesized compounds against 60 human tumor cell lines (NCI60). The most potent derivative exhibited nanomolar antitumor activity on the MCF7 cell line of breast cancer (GI50 = 30 nM) and on the HCT-15 cell line of colon cancer (GI50 = 60 nM).

New Vinca alkaloid derivatives were synthesized to improve the biological activity of the natural alkaloid vindoline. To this end, experiments were performed to link vindoline with various structural units, such as amino acids, a 1,2,3-triazole derivative, morpholine, piperazine and N-methylpiperazine. The structure of the new compounds was characterized by NMR spectroscopy and mass spectrometry (MS). Several compounds exhibited in vitro antiproliferative activity against human gynecological cancer cell lines with IC50 values in the low micromolar concentration range.