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Biological investigation was conducted to study in vitro changes in morphological properties and metabolic activity of human continuous cell lines after treatment with the morphogenetic field hologram information (the field). We used human tumor cell lines, including cervical (HeLa) and lung cancer (A549), as well as one normal fetal lung fibroblasts cell line (MRC-5) to investigate the effect of such treatment. Metabolic activity of investigated cell lines was evaluated by MTT assay. Results showed that MRC-5 cells exposed 3 h to the field had 50% increases in metabolic activity 48 h after treatment in comparison to untreated control cells. Similar but lower effect was observed in both tested tumor cell lines. Changes in cells depended also on the exposure time. Morphology of the cells was examined by visual observations using light microscopy. Metabolic activity was evaluated by MTT assay. Results of this study showed that application of the field has measurable influence on biological systems. [ABSTRACT FROM AUTHOR]

Steroids are good candidates for drug development, thanks to their low general toxicity and possibility for structure modifications connected with change of their activity. Several 16,17-secoandrost-4-ene-16,17a-dinitrile compounds were synthesized and screened for anticancer effect previously, including 6-oxo and 6-hydroxyimino compounds. This research is continued with the attempts for different synthetic strategy and evaluation of anticancer effect mechanism. Synthesis of 3-hydroxyimino compounds was successful, but inseparable mix of isomers was excluded from biological tests. Tested secodinitriles expressed cytotoxic effect on HeLa cervix cancer cells as a model system, with submicromolar to molar IC50 values, where 6-substituted derivatives were more effective. After 72 h treatment with equitoxic concentrations equal IC50 values of test compounds the mechanism of this effect was studied using flow cytometry and specific fluorescent dyes. Modest change in both G0/G1 and G2/M resting phases and change in mitochondrial membrane potential were noticed, while the most pronounced effect was apoptosis induction. Total apoptosis was in range 50.72-58.31 % in all cell samples treated with secodinitriles, compared to 7.44 % in control samples. Total percent of dead cells, including both apoptotic and necrotic, ranged from 55.24 to 65.34 %, compared to 10.68 % in control. Selectivity towards cancer cells is very important feature of these compounds indicating their potential use as lead compounds in the drug development for the treatment of cancers of steroid hormone-dependent tissues. [ABSTRACT FROM AUTHOR]

Four novel conformationally restricted (-)-muricatacin analogues, bearing a methoxy group at the C-5 position and with an alkoxymethyl group as the C-7 side chain, have been synthesised and their in vitro antiproliferative activity was evaluated against a panel of seven human tumour cell lines, as well as a single normal cell line. All analogues (9-12) showed diverse antiproliferative effects against all tested human malignant cell lines, but were devoid of any significant cytotoxicity towards the normal foetal lung fibroblasts (MRC-5). A structure-activity relationship study reveals that the introduction of tetrahydrofuran ring, the replacement of C-8 methylene group in the side chain of muricatacin analogues with the O-8 ether functionality, as well as the length of side chain may be beneficial for the antiproliferative effects of these lactones. All novel analogues were more potent than lead compound, (-)-muricatacin, against HL-60 cell line. [ABSTRACT FROM AUTHOR]

A dicarboxylato-diamide-type compound 2,2'-[(1,2-dioxoethane-1,2--diyl)diimino]dibenzoic acid (H4obbz) (1) was synthesized and characterized. The crystal structure of K2H2obbz·2H2O (2) was determined by X-ray diffracttion analysis. The cytotoxic activities of the compounds were tested against four different cancer cell lines MCF-7, A549, HT-29, HeLa and a human normal cell line MRC-5. The results indicate reasonable dose-dependent cytotoxicity of the ligands that show selectivity against the tested carcinoma and healthy cell lines. Flow cytometric analysis and fluorescence microscopy showed that the most active compound, H4obbz, induced apoptosis and G0/G1 cell cycle arrest, indicating blockage of DNA synthesis as a possible mechanism that triggers apoptosis. Docking and molecular dynamics simulations gave similar responses regarding interactions (binding) between their ligands and chaperon Grp78. The MMGBSA determined ΔG binding energies were in the range from -104 to -140 kJ mol-1. [ABSTRACT FROM AUTHOR]

A divergent synthesis of two novel tiazofurin analogues, 2-(3-deoxy-3-fluoro-β-d-xylofuranosyl)thiazole-4-carboxamide (2) and 2-(3-acetamido-3-deoxy-β-d-xylofuranosyl)thiazole-4-carboxamide (3), has been achieved starting from d-glucose. Both nucleoside analogues were evaluated for their in vitro cytotoxicity against several human leukaemia and solid tumour cell lines. [Copyright &y& Elsevier]

Several (+)-goniofufurone analogues with simplified structures were designed, synthesized and evaluated for their in vitro antitumour activity, against a panel of human tumour cell lines. Dephenylated compounds 2 and 3 demonstrated remarkable antitumour activities, in the cultures of K562 and Raji cells with IC50 values in the range of 3.0-9.3 nM. Each of goniofufurone analogues lacking the tetrahydrofuran ring (4, 5 and 6) strongly inhibited the growth of at least one malignant cell line, with IC50 values in the range of 11-30 nM. Brief structure-activity relationship (SAR) analysis showed that the simplified goniofufurone analogues, designed by removing the phenyl group from C-7, or by opening the THF ring, could show stronger antiproliferative effects compared to control molecules. It is noticeable that analogues 2-8 are completely inactive with respect to the normal MRC-5 cell line. These findings, together with their potent antitumour activities, provide a suitable basis for the development of new and selective antitumour drugs. [ABSTRACT FROM AUTHOR]

Divergent synthesis of novel (-)-goniofufurone mimics with an alkoxymethyl group as the side chain have been accomplished from D-glucose in nine synthetic steps and in overall yields 6.7- 8.7%. Their in vitro antiproliferative activity was evaluated against eight human tumour cell lines as well as a single normal cell line. All analogues demonstrated powerful to good antiproliferative effects toward all malignant cell lines under evaluation. Against HL-60 cell line, all mimics showed increased activities being 27- to 1604-fold more potent than the lead compound, (-)-goniofufurone. Remarkably, the majority of synthesized analogues displayed higher or similar activity as commercial antitumour agent doxorubicin (DOX) against A549 cell line. The most potent compound exhibited 196-fold stronger cytotoxicity than DOX, in the culture of this cell line. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A new total synthesis of cardiobutanolide and two new analogues has been completed. • In vitro antitumour activity of this natural product and analogues was recorded. • (+)-Cardiobutanolide was identified as the most active compound. Abstract A new asymmetric synthesis of the naturally occurring styryl lactone cardiobutanolide and two novel analogues have been achieved starting from d -xylose. The key steps of the synthesis included an initial zinc mediated reductive THF-ring opening, stereoselective olefination and Sharpless asymmetric dihydroxylation. It was shown that cardiobutanolide (1) exhibits promising in vitro antitumour properties against certain human neoplastic cell lines. It was more potent than the commercial anticancer agent doxorubicin against three cell lines (K562, HL-60 and Raji). [ABSTRACT FROM AUTHOR]

A series of new conformationally restricted goniofufurone mimics, bearing an additional 1,3-dioxan ring and a halogen, azido or benzoyloxy functionality at the C-7 position has been designed and synthesized. The Appel reaction was used for replacement of 7-OH group with Cl or Br functions in tricyclic lactone ( 3 ). 7-Iodo derivative ( 3d ) was prepared by using the Ph 3 P/I 2 /2,6-lutidine reagent system. 7-Fluoro group was introduced by treatment of 3 with DAST, while the corresponding 7-azido and 7-benzoyloxy derivatives have been prepared by multistep sequences. Synthesized products were evaluated for their ability to inhibit growth of selected human malignant cell lines. Structure-activity relationships demonstrated that the nature of a substituent at the C-7 position could enhance the antiproliferative activity of the analogues. The preliminary study on the mechanisms indicated that all synthesized compounds induced apoptosis in 61–77% of K562 cells. [ABSTRACT FROM AUTHOR]

[Display omitted] • Protulactone A. • Natural product. • X-ray analysis. • Antiproliferative activity. Synthesis of protulactone A (PLA, 1) and twelve of its analogues have been achieved starting from d -galactose. PLA was isolated in the crystalline state, and its crystal structure was determined utilizing X-ray crystallography, which confirmed the assumed stereochemistry at all stereocenters. All tested compounds displayed antiproliferative activity against a panel of tumour cell lines, and all of them were non-cytotoxic toward the normal cells (MRC-5). Natural product PLA (1) was the most active against the K562 and MCF-7 cell lines (IC 50 6.52 and 2.20 μM, respectively). Some of the synthesized derivatives showed very potent cytotoxicity, especially analogues 11 , 13 and 15 (IC 50 1.08–1.14 μM against MCF-7), and 9 and 14 (IC 50 1.29 and 1.64 μM against K562). SAR analysis indicated important structural motifs for antiproliferative activity. Unfortunately, PLA (1), its C-7 epimer (2) and demethylated analogue (3) did not display a significant antimicrobial activity (two Gram-positive and two Gram-negative bacteria and one fungal strain) and they also cannot affect the ability to modulate bacterial communication. [ABSTRACT FROM AUTHOR]

Abstract: This paper describes a straightforward divergent synthesis of (+)-goniofufurone mimics (4, 5 and 6) starting from d-xylose. In a preliminary bioassay, analogues 4 and 5 exhibited a submicromolar antiproliferative activity towards HL-60 cells, while the corresponding parent compound 1 was completely inactive against this cell line. At the same time, these molecules showed approximately 10-fold stronger cytotoxicity in the same cell line when compared to the standard anticancer drug doxorubicin (DOX). Analogue 6 displayed 18- and 3-fold higher potency in Raji cell line when compared to control compounds 1 and DOX, respectively. A new divergent route for the preparation of (+)-goniofufurone (1) and (+)-crassalactone C (3) from d-xylose is also disclosed. [Copyright &y& Elsevier]

Starting from 17(Z)-picolinylidene-androst-5-en-3β-yl acetate 1, the new derivatives 4-8 were synthesized. By oxidation of 3β-hydroxy derivative 2 with Jones reagent the corresponding 17(Z)-picolinylidene-androst-4-ene-3,6-dione 4 was obtained. The Oppenauer oxidation of 2 yielded 4-en-3-one derivative 3, which reacted with potassium-t-butoxide in t-butanol to give 4-ene-3,6-dione 4 and 4-hydroxy-4,6-dien-3-one 5 derivatives. Nitration of compound 1 afforded 6-nitro-5-ene derivative 6. The reaction of compound 3 with NaBH4 in ethanol afforded stereoselectively the 3β-hydroxy-4-ene derivative 7, the acetylation of which gave 3β-acetoxy derivative 8 whereas 17-picolinylidene derivatives 9-14 have been synthesized earlier. Compounds 4-8 were tested on potential inhibitory activity against the enzyme aromatase. Satisfactory inhibitory activity showed compounds 4, 5, 7 and 8. Cytotoxicity in vitro against three tumor cell lines (human breast adenocarcinoma ER+, MCF-7 as well as human breast adenocarcinoma ER-, MDA-MB-231 and prostate cancer AR-, PC-3) and normal fetal lung fibroblasts, MRC-5, of compounds 1-14 was also evaluated. Strong cytotoxic activity showed compound 5 against MDA-MB-231 (IC50 9.3 μM) and compound 7 against PC-3 (IC50 10.1 μM). All compounds were not toxic to healthy MRC-5 cells. [ABSTRACT FROM AUTHOR]

Abstract: Enantiodivergent formal synthesis of (+)- and (−)-muricatacins from d-xylose has been accomplished through utilization of the latent plane of symmetry present in the starting monosaccharide. This approach was extended to the preparation of two novel (+)- and (−)-muricatacin 7-oxa analogs (2 and ent-2, respectively), which showed in vitro antitumor activity toward some human malignant cells. The analog ent-2 showed a powerful antiproliferative activity against the K562 cell line, being 36-fold more potent than the standard cytotoxic agent, doxorubicin. Compound 2, however, showed a powerful cytotoxic activity against HL-60 cells, being more than 17-fold more potent with respect to the reference compound. [Copyright &y& Elsevier]

Abstract: A new tiazofurin analogue, 2-(3-amino-3-deoxy-β-d-xylofuranosyl)thiazole-4-carboxamide (3), was synthesized starting from d-glucose and evaluated for its in vitro antiproliferative activity against a panel of human tumour cell lines. Compound 3 exhibited the most powerful cytotoxicity against K562 cells, being approximately 100-fold more potent than tiazofurin. This analogue was also active against Jurkat, HT-29 and HeLa malignant cells, with respective IC50 values being ca. 2-, 27- and 17-fold lower than those observed for tiazofurin. Remarkably, compound 3 did not exhibit any significant cytotoxicity towards normal foetal lung MRC-5 cell line. [Copyright &y& Elsevier]

Abstract: A divergent approach to the 7-oxa (–)-muricatacin analogue 2, the corresponding (+)-enantiomer ent-2 and the furanolactone 3 is reported starting from d-xylose. The resulting lactones have shown a potent and selective in vitro cytotoxicity against certain human neoplastic cell lines. [Copyright &y& Elsevier]

Fifteen new analogues of (−)-cleistenolide (1) with aromatic ester groups at the C-6 position were designed and synthesized by multistep sequences. Steglich esterification of δ-pyrone 10 with selected aromatic acids (benzoic, cinnamic, and 4-substituted cinnamic acids) gave the corresponding 6- O -acyl derivatives 11 – 15. An original method was developed for the selective conversion of the primary benzyloxy group into the corresponding acetoxy function, giving five new bioisosteres (16 – 20) for biological testing. Finally, the dibenzyl derivative 11 was converted to the corresponding diacetate 2 using the AcBr/Zn(OTf) 2 reagent system. For the transformation of compounds 12 – 15 into the corresponding 4,7-diacetates (3 – 6), in addition to Zn(OTf) 2 , it was necessary to use FeCl 3 as a co-catalyst. The cleistenolide analogues thus obtained were tested for their in vitro antitumour activity The majority of compounds showed higher potency compared to lead 1 toward five of six investigated human tumour cell lines, but were almost completely inactive in the culture of normal foetal fibroblasts (MRC-5). The most potent antiproliferative activity was shown by 4,7-di- O -benzyl derivatives 13 and 14 , with IC 50 values of 0.04 (HeLa) and 0.09 μM (Jurkat), respectively. Preliminary SAR analysis revealed some of the structural features important for the activity of this class of compounds. These are: the presence of unsubstituted cinnamate function at the C-6 position and the presence of an acetoxy group at the C-4 position. New analogues of (−)-cleistenolide were designed, synthesized and evaluated for their antitumour activity in vitro. [Display omitted] • New cleistenolide analogues were designed, synthesized and tested for their in vitro cytotoxicity. • A new method for selective conversion of the primary OBn to AcO functions was developed. • Ten analogues are more active than doxorubicin against A549 cells. • Analogues are inactive to normal MRC-5 cells, and specific for tumour cells. [ABSTRACT FROM AUTHOR]

• New steroidal lactones with modifications in positions C5 and C6 were synthesized. • Compounds were tested on six tumor cell lines for their cytotoxic properties. • Compounds were evaluated for affinity to the ligand binding domains of ERα/β or AR. • The most active compounds were studied for their apoptosis-induction potential. • Molecular docking predicts binding of polyhydroxy compound to EGFR tyrosine kinase. A series of 5,6-modified steroidal d -homo lactones, comprising of halogenated and/or oxygenated derivatives, was synthesized and evaluated for potential anticancer properties. Preparation of many of these compounds involved investigating alternative synthetic pathways. In silico ADME testing was performed for both novel and some previously synthesized compounds. Calculated physicochemical properties were in accordance with the Lipinski, Veber, Egan, Ghose and Muegge criteria, suggesting the potential of these molecules as orally active agents. Cytotoxicity of the synthesized steroid derivatives was tested on six tumor and one normal human cell line. None of the investigated derivatives was toxic to non-cancerous MRC-5 control cells. Most of the compounds showed significant cytotoxicity against the treated cancer cell lines. Most notably, the 3β,5α,6β-trihydroxy derivative exhibited strong cytotoxicity against multiple cell lines (MCF-7, MDA-MB-231 and HT-29), with the highest effect observed for lung adenocarcinoma (A549) cells, for which this steroid was more cytotoxic than all of the three commercial chemotherapeutic agents used as reference compounds. Molecular docking suggests the 3β,5α,6β-trihydroxy derivative could bind the EGFR tyrosine kinase domain with high affinity, providing a potential mechanism for its cytotoxicity via inhibition of EGFR signaling. The most active compounds were further studied for their potential to induce apoptosis by the double-staining fluorescence method; where the 5α,6β-dibromide, 5α,6β-dichloride and 3β,5α,6β-triol induced apoptotic changes in all three treated cell lines: MDA-MB-231, HT-29 and A549. To predict interactions with nuclear steroidal receptors, affinity for the ligand binding domains of ERα, ERβ and AR was measured using a yeast-based fluorescence assay. The 5β,6β-epoxide, dibromide and 5α-hydroxy-3,6-dioxo derivatives showed affinity for ERα, while the 5α-fluoro-6β-hydroxy and 3β-acetoxy-5α,6β-dihydroxy derivatives were identified as ERβ ligands. None of the tested compounds showed affinity for AR. Structure-activity relationships of selected compounds were also examined. [ABSTRACT FROM AUTHOR]

A new, modified total synthesis of (−)-cleistenolide (1) and sixteen new analogues or derivatives was achieved starting from commercially available 1,2- O -isopropylidene-α- d -glucofuranose. The synthesis of 1 proceeds in six steps and 67% overall yield, using single-carbon atom degradation of a protected chiral precursor, (Z)-selective Wittig olefination, and acid catalyzed δ-lactonization. A new Lewis acid promoted procedure for one-pot O -debenzylation/ O -acylation has been developed to complete the synthesis of natural product 1 and selected analogues. The synthesized compounds were tested in vitro to evaluate their cytotoxicity against K562, HL-60, Jurkat, Raji, MCF-7, MDA-MB 231, HeLa, A549, and MRC-5 cell lines. All (−)-cleistenolide analogues exhibited significantly higher cytotoxicity than lead 1 against the majority of cell lines tested. Most of the synthesized compounds are more active than doxorubicin on at least one malignant cell line, but were almost completely inactive against normal MRC-5 cells. The structural features of the tested compounds responsible for their antiproliferative activity have been identified by preliminary SAR analysis. Image 1 New synthesis of cleistenolide (1) was achieved through 6 steps with a total yield of 67%. Twenty analogues of natural product 1 were designed, synthesized, and evaluated for their antiproliferative activity against eight tumour cell lines. • New synthesis of cleistenolide (1) was achieved over 6 steps and 67% overall yield. • Sixteen new cleistenolide analogues were prepared and tested for anticancer activity. • All analogues showed higher potency than lead 1 and are non-toxic to normal MRC-5 cells. • Structural features responsible for antitumour activity were identified by SAR analysis. [ABSTRACT FROM AUTHOR]

• New A-homo lactam D-homo lactone androstane derivative was synthesized. • Strong cytotoxic and anti-inflammatory activities were demonstrated. • New androstane derivative induced apoptosis more than Formestane and Doxorubicin. • An in silico ADME analysis showed that the compounds possess drug-like properties. This paper describes the synthesis of a new A-homo lactam D-homo lactone androstane derivative from dehydroepiandrosterone. To evaluate the impact of the introduction of nitrogen in the parental scaffold on biological activity, a new androstane enamide-type lactam derivative was prepared and characterized. The new compound as well as starting compounds were screened for cytotoxic, anti-angiogenic and anti-inflammatory activities using several human cancer cell lines (MCF-7, MDA-MB-231, PC3, CEM, G-361, HeLa), endothelial (HUVEC) and non-tumour (MRC-5 and BJ) cell lines. Strong cytotoxic and anti-inflammatory activity with a broad therapeutical window was demonstrated by the A-homo lactam D-homo lactone androstane derivative. The induction of apoptosis in treated PC3 cultures was confirmed using apoptotic morphology screening and a fluorescent double-staining method. New A-homo lactam D-homo lactone androstane derivative induced apoptosis more than the tested reference compounds, Formestane and Doxorubicin. An in silico ADME analysis showed that the compounds possess drug-like properties. [ABSTRACT FROM AUTHOR]