Marta Świtalska

Synthesis and in vitro antiproliferative activity of new 11-aminoalkylamino-substituted 5H- and 6H-indolo(2,3-b)quinolines; structure-activity relationships of neocryptolepines and 6-methyl congeners

The present report describes the synthesis and antiproliferative evaluation of certain 11-aminoalkylamino-substituted 5H- and 6H-indolo[2,3-b]quinolines and their methylated derivatives. These 5-Me- and 6-Me-indolo[2,3-b]quinoline derivatives 10-14, 20 were prepared by amination at the C-11 position of the 11-chloro-5-methyl-5H- and 11-chloro-6-methyl-6H-indolo[2,3-b]quinolines with different substituents on the quinoline ring. The 11-aminoalkylaminomethylated 23, the homologue of 11, was prepared from the same intermediate for a further SAR study. These intermediates are accessible from 4-substituted anilines or their N-methylated analogues and methyl indole-3-carboxylate as a counterpart. The in vitro antiproliferative assay indicated that the 5-methylated derivatives 10-14 are more cytotoxic than their respective 6-methylated 6H-indolo[2,3-b]quinoline derivatives 20. Among them, N-(3-aminopropyl)-2-bromo-5-methyl-5H-indolo[2,3-b]quinolin-11-amine 12f was the most cytotoxic with a mean IC(50) value of 0.12 μM against human leukemia MV4-11 cell line, and also exhibited selective cytotoxicities against A549 (lung cancer), HCT116 (colon cancer) cell lines and normal fibroblast BALB/3T3 with IC(50) values of 0.543, 0.274 and 0.869 μM, respectively. The binding constant of products 12f and 20f to salmon fish sperm DNA were also evaluated using UV-vis absorption spectroscopy, indicating intercalation binding with a constant of 2.93×10(5) and 3.28×10(5)Lmol(-1), respectively.

Synthetic conjugates of genistein affecting proliferation and mitosis of cancer cells

This paper describes the synthesis and antiproliferative activity of conjugates of genistein (1) and unsaturated pyranosides. Constructs linking genistein with a sugar moiety through an alkyl chain were obtained in a two-step synthesis: in a first step genistein was converted into an intermediate bearing an ω-hydroxyalkyl substituent, containing two, three or five carbon atoms, at position 7, while the second step involved Ferrier glycosylation reaction, employing glycals. Antiproliferative activity of several genistein derivatives was tested in cancer cell lines in vitro. The most potent derivative, Ram-3 inhibited the cell cycle, interacted with mitotic spindles and caused apoptotic cell death. Neither genistein nor the sugar alone were able to influence the mitotic spindle organization. Our results indicate, that conjugation of genistein with certain sugars may render the interaction of derivatives with new molecular targets.

Microbial transformation of (+)-nootkatone and the antiproliferative activity of its metabolites

Six metabolites were obtained as a result of microbial transformation of (+)-nootkatone (1) by the fungal strains: Botrytis, Didymosphaeria, Aspergillus, Chaetomium and Fusarium. Their structure were established as (+)-(4R,5S,7R,9R)-9α-hydroxynootkatone (2), (+)-(4R,5S,7R)-13-hydroxynootkatone (3) and (+)-(4R,5S,7R,9R,11S)-11,12-epoxy-9α-hydroxynootkatone (4), (+)-(4R,5S,7R,11S)-11,12-epoksynootkatone (5), (+)-(4R,5S,7R)-11,12-dihydroxynootkatone (6) and (+)-(4R,5S,7R)-7,11,12-trihydroxynootkatone (7) on the basis of their spectral data. Two products: (4) and (7) were not previously reported in the literature. The antiproliferative activity of (+)-nootkatone (1) and isolated metabolites (2-7) of its biotransformation has been evaluated.

Synthesis and biological evaluation of new amino acid and dipeptide derivatives of neocryptolepine as anticancer agents.

The syntheses of neocryptolepine derivatives containing an amino acid or a dipeptide at the C-9 position and their evaluation for antitumor activity in vitro and in vivo are reported. To establish the influence of an amino acid or a peptide on the physicochemical properties of 5H-indolo[2,3-b]quinoline (DiMIQ), lipophilic and hemolytic properties were investigated. Most of the compounds displayed a high antiproliferative activity in vitro and strongly inhibited growth of tumor in mice compared to cyclophosphamide. The attachment of the hydrophilic amino acid or the peptide to the hydrophobic DiMIQ increased its hydrophilic properties and decreased its hemolytic activity. The glycylglycine conjugate (7a) was the most promising derivative. It strongly inhibited the growth of the tumor in mice (at dose 50 mg kg(-1) day(-1) it inhibited the tumor growth by 46-63% on days 11-16 and by 29-43% on days 18-23) and significantly decreased hemolytic activity and lowered the in vivo toxicity compared to DiMIQ.

Synthesis and in vitro antiproliferative activity of new 11-aminoalkylamino-substituted chromeno[2,3-b]indoles

To search for new biological activities of the chromeno[2,3-b]indoles, the 5-oxa analog of the indolo[2,3-b]quinolines that are known to have a potent antitumor activity, a series of 11-amino derivatives with various substituents at the C-2 position were prepared. The synthesis of the chromeno[2,3-b]indole structure involves the cyclization of 2-phenoxy-3-indolecarboxylates 3, accessible from the indole-3-carboxylate 1 and phenols 2, producing the chromeno[2,3-b]indol-11(6H)-ones 4, which is followed by dehydroxychlorination with phosphorus oxychloride to afford the 11-chlorochromeno[2,3-b]indoles 5. The treatment of 5 with various amines produced the corresponding 11-aminated chromeno[2,3-b]indoles 6, while some of the 11-ω-aminoalkylamino derivatives 6 were transformed into the 11-ω-sulfonylaminoalkylamino derivatives 8. The antiproliferative activity of these 11-aminochromeno[2,3-b]indoles 6 and 8 in vitro were tested using MV4-11 (human leukemia), A549 (lung cancer), HCT116 (colon cancer), and the normal mice fibroblast (BALB/3T3) and their potencies were described.

Design, synthesis, and in vitro cancer cell growth inhibition evaluation and antimalarial testing of trioxanes installed in cyclic 2-enoate substructures

A novel series of 1,2,4-trioxanes were synthesized from 2H-pyrans via photooxidation, and their antiproliferative and growth factor inhibitory activity has been investigated across a variety of human cancer cell lines. Compounds 5k, 5l, 5s, 7a and 7c exhibited the highest activity and selectivity against a human leukemia (MV4-11) cell line (IC₅₀ = 0.5 μM). Compound 5o showed the highest growth factor inhibitory activity against a melanoma (LOX-IMVI) cancer cell line (GI₅₀ = 1.0 μM). A SAR study has confirmed the importance of the 1,2,4-trioxane unit as a pharmacophore for anticancer activity. The computer-assisted database analysis, COMPARE, has suggested that the compounds have unique mechanisms of actions that were different from those of known anticancer drugs. Some of the selected trioxanes were tested against the NF54 strain, albeit showing weak antiplasmodial activity. The molecular docking of trioxanes and hemin reveals that a short distance (1.30 Å) leads to their physical contact. The UV-vis spectroscopic analysis ensured the definite complexation between 1,2,4-trioxanes and hemin. The role of hemin-trioxane interaction in the hemin-induced oxidative damage has been studied using methylene blue as a substrate by UV-vis spectroscopy.

The in-vitro antiproliferative effect of PRI-2191 and imatinib applied in combined treatment with cisplatin, idarubicin, or docetaxel on human leukemia cells.

Imatinib mesylate (Gleevec, STI571) is a specific inhibitor of the Bcr/Abl fusion tyrosine kinase that exhibits potent antileukemic effects in chronic myelogenous leukemia. Bcr/Abl-positive K562 and Bcr/Abl-negative HL-60 human leukemia cells were used to investigate the effect of PRI-2191, a calcitriol analog, on the biological effects of imatinib combined with other anticancer drugs.The results show that PRI-2191 enhances the antiproliferative effect of imatinib on HL-60 cells. When these two agents together are applied with either docetaxel or cisplatin, but not with idarubicin, the antiproliferative effect could still be enhanced. Moreover, when the interaction between the chemotherapy agents was antagonistic or additive, PRI-2191 could even shift it to synergism. This effect correlated with an accumulation of HL-60 cells in the G0/G1 phase of the cell cycle and a decrease in the percentage of cells in the G2/M and S stage in the ternary combinations used. PRI-2191 did not influence apoptosis induced by imatinib alone or in ternary combinations with all the chemotherapy agents used. These results may suggest that the stronger antiproliferative effect of the combined treatment with PRI-2191 on HL-60 cells is related to cell cycle arrest rather than to the induction of apoptosis.

Design, synthesis, and biological evaluation of artemisinin-indoloquinoline hybrids as potent antiproliferative agents.

A series of artemisinin-indoloquinoline hybrids were designed and synthesized in an attempt to develop potent and selective anti-tumor agents. Compounds 7a–7f, 8 and 9 were prepared and characterized. Their antiproliferative activities against MV4-11, HCT-116, A549, and BALB/3T3 cell lines in vitro were tested. Nearly all of the tested compounds (7–9, except for compounds 7d and 7e against HCT-116) showed an increased antitumor activity against HCT-116 and A549 cell lines when compared to the dihydroartemisinin control. Especially for the artemisinin-indoloquinoline hybrid 8, with an 11-aminopropylamino-10H-indolo[3,2-b]quinoline substituent, the antiproliferative activity against the A549 cell line had improved more than ten times. The IC50 value of hybrid 8 against A549 cell lines was decreased to 1.328 ± 0.586 μM, while dihydroartemisin showed IC50 value of >20 µM in the same cell line. Thus, these results have proven that the strategy of introducing a planar basic fused aromatic moiety, such as the indoloquinoline skeleton, could improve the antiproliferative activity and selectivity towards cancer cell lines.

Searching for new derivatives of neocryptolepine: Synthesis, antiproliferative, antimicrobial and antifungal activities

A series of novel amino acid and dipeptide derivatives of neocryptolepine were synthesized and tested for their antimicrobial, antifungal and antiproliferative activity in vitro against cancer cell lines (KB, A549, MCF-7, LoVo) and normal mice fibroblast cells (BALB/3T3). Biological evaluation revealed that almost all of the new compounds displayed high antiproliferative activity against the tested cells and moderate to potent antibacterial activities. Interestingly, these compounds were active against Candida albicans biofilms at doses significantly lower than those required against free-floating planktonic fungal cells. The most promising compounds are derivatives with glycine and L-proline as a substituent both at 2 and at 9 position of 5H-indolo[2,3-b]quinoline. In general, these new compounds (2a, 3a, 6a and 7a) showed the highest dual action against cancer lines and infectious pathogenic microbes in vitro.

Vitamin D Analogs Potentiate the Antitumor Effect of Imatinib Mesylate in a Human A549 Lung Tumor Model.

In previous papers, we presented data on studies on the anticancer activity of the vitamin D3 analogs, named PRI-2191 and PRI-2205, in different cancer models. In this study, we showed the improved antiproliferative activity of a combination of imatinib mesylate (Gleevec, GV) and cytostatic agents in in vitro studies, when used with a third compound, namely PRI-2191, in an A549 human lung cancer model. Furthermore, we analyzed the influence of both PRI-2191, as well as PRI-2205 on the anticancer activity of GV in mice bearing A549 tumors. The route of PRI-2191 analog administration showed a significant impact on the outcome of GV treatment: subcutaneous injection was more efficient and less toxic than oral gavage. Moreover, both vitamin D compounds increased the anticancer activity of GV; however, they might also potentiate some adverse effects. We also evaluated in tumor tissue the expression of VEGF, PDGF-BB, vitamin D receptor, CYP27B1, CYP24, p53 and Bcl-2, as well as PDGF receptors: α and β. We observed the upregulation of p53 expression and the downregulation of Bcl-2, as well as VEGF in A549 tumors as a result of the tested treatment. However, vitamin D analogs did not significantly influence the expression of these proteins.