Nature-Inspired 1-Phenylpyrrolo[2,1-a]isoquinoline Scaffold for Novel Antiproliferative Agents Circumventing P-Glycoprotein-Dependent Multidrug Resistance.

Previous studies have shown that some lamellarin-resembling annelated azaheterocyclic carbaldehydes and related imino adducts, sharing the 1-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (1-Ph-DHPIQ) scaffold, are cytotoxic in some tumor cells and may reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). Herein, several novel substituted 1-Ph-DHPIQ derivatives were synthesized which carry carboxylate groups (COOH, COOEt), nitrile (CN) and Mannich bases (namely, morpholinomethyl derivatives) in the C2 position, as replacements of the already reported aldehyde group. They were evaluated for antiproliferative activity in four tumor cell lines (RD, HCT116, HeLa, A549) and for the ability of selectively inhibiting P-gp-mediated MDR. Lipophilicity descriptors and molecular docking calculations helped us in rationalizing the structure-activity relationships in the P-gp inhibition potency of the investigated 1-Ph-DHPIQs. As a main outcome, a morpholinomethyl Mannich base (8c) was disclosed which proved to be cytotoxic to all the tested tumor cell lines in the low micromolar range (IC50 < 20 µM) and to inhibit in vitro the efflux pumps P-gp and MRP1 responsible for MDR, with IC50s of 0.45 and 12.1 µM, respectively.

Homobivalent Lamellarin-Like Schiff Bases: In Vitro Evaluation of Their Cancer Cell Cytotoxicity and Multitargeting Anti-Alzheimer's Disease Potential.

Marine alkaloids belonging to the lamellarins family, which incorporate a 5,6-dihydro-1-phenylpyrrolo[2,1-a]isoquinoline (DHPPIQ) moiety, possess various biological activities, spanning from antiviral and antibiotic activities to cytotoxicity against tumor cells and the reversal of multidrug resistance. Expanding a series of previously reported imino adducts of DHPPIQ 2-carbaldehyde, novel aliphatic and aromatic Schiff bases were synthesized and evaluated herein for their cytotoxicity in five diverse tumor cell lines. Most of the newly synthesized compounds were found noncytotoxic in the low micromolar range (<30 µM). Based on a Multi-fingerprint Similarity Search aLgorithm (MuSSeL), mainly conceived for making protein drug target prediction, some DHPPIQ derivatives, especially bis-DHPPIQ Schiff bases linked by a phenylene bridge, were prioritized as potential hits addressing Alzheimer's disease-related target proteins, such as cholinesterases (ChEs) and monoamine oxidases (MAOs). In agreement with MuSSeL predictions, homobivalent para-phenylene DHPPIQ Schiff base 14 exhibited a noncompetitive/mixed inhibition of human acetylcholinesterase (AChE) with Ki in the low micromolar range (4.69 µM). Interestingly, besides a certain inhibition of MAO A (50% inhibition of the cell population growth (IC50) = 12 µM), the bis-DHPPIQ 14 showed a good inhibitory activity on self-induced ß-amyloid (Aß)1-40 aggregation (IC50 = 13 µM), which resulted 3.5-fold stronger than the respective mono-DHPPIQ Schiff base 9.

Synthesis and antitumor activity of daunorubicin conjugates with of 3,4-methylendioxybenzaldehyde.

The design of hybrid (chimeric) molecules containing two different pharmacophores connected via a spacer (linker) is a promising approach to the functionalization of natural compounds and potentially of drug molecules. These are important examples for the use of this approach with anthracycline antibiotics. The use of this methodology may help to eliminate some of the drawbacks of anthracycline drugs, e.g., high cardiotoxicity and MDR development.

2,4,5-Tris(alkoxyaryl)imidazoline derivatives as potent scaffold for novel p53-MDM2 interaction inhibitors: Design, synthesis, and biological evaluation.

Imidazoline-based small molecule inhibitors of p53-MDM2 interaction intended for the treatment of p53 wild-type tumors are the promising structures for design of anticancer drugs. Based on fragment approach we have investigated a key role of substituents in cis-imidazoline core for biological activity of nutlin family compounds. Although the necessity of the substituents in the phenyl rings of cis-imidazoline has been shown, there are no studies in which the replacements of a halogen by other substituents have been investigated. A series of simple cis-imidazoline derivatives containing halogen, hydroxy and alkoxy-substituents were synthesized. The biological activity of the compounds was studied using assays of cytotoxicity (MTT) and p53 level. It was found that the hydroxyl-derivatives were not cytotoxic whereas the alkoxy analogues were the same or more active as halogen-substituted compounds in cell viability test. The synthesized alkoxy derivatives induced an increase of p53 level and did not promote necrotic cell death in the concentration up to 40 µM.

Synthesis and biological evaluation of 3-substituted 2-oxindole derivatives as new glycogen synthase kinase 3ß inhibitors.

Glycogen synthase kinase 3ß (GSK-3ß) is a widely investigated molecular target for numerous diseases including Alzheimer's disease, cancer, and diabetes mellitus. Inhibition of GSK-3ß activity has become an attractive approach for treatment of diabetes and cancer. We report the discovery of novel GSK-3ß inhibitors of 3-arylidene-2-oxindole scaffold with promising activity. The most potent compound 3a inhibits GSK-3ß with IC50 4.19 nM. In a cell-based assay 3a shows no significant leucocyte toxicity at 10 µM and is moderately cytotoxic against A549 cells. Compound 3a demonstrated high antidiabetic efficacy in obese streptozotocin-treated rats improving glucose tolerance at a dose of 50 mg/kg body weight thus representing an interesting lead for further optimization.

The influence of substituents on the reactivity and cytotoxicity of imidazothiazolotriazinones.

A series of tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7(1H, 6H)-diones were synthesized via the reaction of imidazotriazinethiones and bromoacetic acid followed by condensation with isatins. Amidine skeletal rearrangement of 3,3a,9,9a-tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7 (1H, 6H)-diones into 1,3a,4,9a-tetrahydroimidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazine-2,8 (3H, 7H)-diones under KOH treatment has been studied. The influence of substituents at positions 1,3,3a,6,9a of imidazothiazolotriazine on the ability to undergo rearrangement was analyzed based on experimental data and theoretical calculations. Both imidazothiazolo[3,2-b]triazines and their rearrangement products were evaluated for their cytotoxic activity against rhabdomyosarcoma, A549, HCT116 and MCF7 human cancer cell lines by MTT assay. Among the derivatives, 1,3-diethyl-6-[1-(2-propyl)-2-oxoindolin-3-ylidene]-3,3a,9,9a-tetrahydroimidazo [4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7(1H, 6H)-dione 4i was found to have the highest antiproliferative activity toward the tested cell lines (4i: [Formula: see text], 2.29, 0.47 and [Formula: see text], respectively). The [Formula: see text] value of compound 4i against normal human embryonic kidney cells HEK293 was [Formula: see text], which appeared to be 6-41-fold higher than [Formula: see text] values of 4i against human cancer cells.

Synthesis and biological evaluation of new substituted thioglycolurils, their analogues and derivatives.

A novel series of substituted N-aminothioglycolurils was synthesized by tandem hydrazone formation - ring contraction reaction of 3-thioxoperhydroimidazo[4,5-e]-1,2,4-triazin-6-ones with (E)-3-phenyl(furan-2-yl)acrylaldehyde derivatives. S-Alkyl substituted N-aminothioglycolurils were prepared through alkylation of corresponding thioglycolurils with iodoalkane or 4-chlorobenzylchloride. Methylthio group in S-methyl derivatives can be substituted with hydroxyl group in acid medium to give N-aminoglycolurils. Representative compounds were evaluated for their cytotoxic activity against RD, A549, HCT116 and MCF7 human cancer cell lines by MTT-assay and screened for their antifungal activity against phytopathogenic fungi using the mycelium growth inhibition method in vitro. Among the derivatives, 4-((E)-((E)-3-(2-Methoxyphenyl)allylidene)amino)-3-methyl-1-phenylthioglycoluril 8i was found to have the highest antiproliferative activity toward the RD and HCT116 cell lines (8i: IC50 = 0.02 and 0.012 µM, respectively), which exceeded cytotoxicity of reference drugs. 1,3-Diethyl-4-((E)-((E)-3-(2-methoxyphenyl)allylidene)amino)thioglycoluril 8l showed the most marked activity toward A549 cells (8l: IC50 = 0.61 µM) compared to reference drugs. The IC50 values of thioglycolurils 8i,l against normal human embryonic kidney cells HEK293 were 0.23 and 86.11 µM, respectively, exceeding the IC50 values of this compound toward the RD, HCT116 (8i) and A549 cells (8l) by one-two orders of magnitude. Experiments with annexin showed that compounds 8b,i,l induced apoptosis in Jurkat cells (acute T cell leukemia). Alkylthioderivatives 12a,13a displayed the strongest antifungal action against R. solani, F. oxysporum, and F. moniliforme exceeding those of triadimefon.

Substituted N-aminothioglycolurils containing thiosemicarbazone moiety and their cytotoxic activity in vitro.

A library of hybrid molecules bearing thioglycoluril and (hetero)aromatic aldehyde thiosemicarbazone moieties was synthesized via a tandem hydrazone formation-ring contraction reaction of 5,7-dialkyl-3-thioxoperhydroimidazo[4,5-e]-1,2,4-triazin-6-ones with (hetero)aromatic aldehydes. All synthesized compounds were tested for their cytotoxic activity against rhabdomyosarcoma, A549, and MS human cancer cell lines by MTT-assay. Among the derivatives, (E)-4-benzylideneamino-1,3-dimethyl-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one 1f was found to have the most marked antiproliferative activity toward the tested cell lines (1f: IC[Formula: see text] 23.7, and 6.4 [Formula: see text]M, respectively). The IC[Formula: see text] value of thioglycoluril 1f against normal human embryonic kidney cells HEK293 was 72.5 [Formula: see text]M, which appeared to be 3-11-fold higher than IC[Formula: see text] values of 1f against human cancer cells.

Synthesis, transformation and biological evaluation of 2,3-secotriterpene acetylhydrazones and their derivatives.

It has been previously shown that semi-synthetic A-secotriterpene acetylhydrazones of 1-cyano-28-methoxy-28-oxo-2,3-seco-2-norlup-20(29)-en-3-al and 1-cyano-2,3-seco-2-nor-19ß,28-epoxy-18αH-olean-3-al (1, 2) inhibit the vesicular stomatitis virus (VSV) replication. To improve the antiviral activity against VSV, structural modifications of compounds 1 and 2 were performed, and new A-secoderivatives containing the acetylhydrazone fragment were obtained from betulonic acid and its methyl ester, allobetulone, and 3-oxo-18ßH-glycyrrhetinic acid methyl ester. The inhibitory effects of these compounds on VSV replication in porcine embryo kidney (PEK) cells were determined after infection. It was shown that introduction of the 3'-acetyl-5'-methyl-1',3',4'-oxadiazoline fragment into lupane triterpene structures lead to an increase in the antiviral activity of A-secotriterpene derivatives. However, the presence of a heterocyclic moiety enhanced toxic activity and reduced the therapeutic indices of these agents. Investigation in the anti-proliferative activity of the heterocyclic derivatives has shown high sensitivity of A-549, MS and RD tumor cell lines to lupane (R)-oxadiazoline 11a. The pro-apoptotic effect of 11a was confirmed by the AnnexinV/PI analysis.