New pseudo-C-nucleosides with pyrazole or tetrazole aglycones, bearing [3.3.0]furofuranone or [3.3.0]furodioxole rings as sugar mimics, were synthesised through a multistep sequence starting from d-glucose. The key step in the synthesis of pyrazole derivatives was the 1,3-dipolar cycloaddition of unsaturated esters 9 and 10 with diazomethane, yielding 2-pyrazoline 11 as a mixture of stereoisomers. Treatment of 11 with a solution of chlorine in carbon tetrachloride yields the pyrazole 12, which is subsequently converted to the pseudo-C-nucleoside 13 after treatment with saturated ammonia in methanol. Esterification of 13 with cinnamic or 4-fluorocinnamic acid gave the hybrids 14 and 16. Hydrolytic removal of the 1,2-isopropylidene protective group from 13 and 16, followed by cyclocondensation of the resulting lactols with Meldrum's acid, gave the [3.3.0]furofuranones 15 and 17. Using a similar reaction sequence, d-glucose was converted into the corresponding tetrazole derivatives 21 and 23. The key step in this synthesis is the cycloaddition of suitably functionalized urononitriles with azide anion to build the tetrazole ring. Some of the pseudo-C-nucleosides exhibited potent cytotoxicity against certain human tumour cell lines. Structural features important for the antiproliferative activity of these analogues were identified by SAR analysis. Biological effects of three compounds with strong cytotoxic response (14, 17 and 30) were investigated. The induction of apoptosis was assessed using several methods, including cell cycle flow cytometry analysis, double-fluorescent staining, and Annexin V flow cytometry. The results showed the potential of compound 14 to induce apoptosis in the most sensitive tumour cell line. The results suggest that these three compounds with strong selective cytotoxicity are good candidates for developing effective anticancer drugs.

Herein, the modified synthesis of natural lactone (-)-cleistanolate (1) and its enantiomer (ent-1), along with the synthesis of six new analogues (3, 10, 11, 12, 13, ent-3), is presented. The antiproliferative activity of natural product 1 and its 22 analogues with lactone moiety was evaluated in vitro against eight human tumour cell lines and one normal cell line. SAR analysis revealed structural characteristics important for the activity of these types of compounds. The synthesized analogues are completely inactive toward the normal MRC-5 cell line. Their selectivity indexes (SI) range from 2.98 to 891.64. Furthermore, antimicrobial potential and inhibition of human acetyl- and butyrylcholinesterases of 1 and selected compounds have been evaluated.

Several new goniofufurone (1) and 7-epi-goniofufurone (2) mimics in which the benzene ring has been replaced with a thiazole residue have been designed, synthesized and evaluated for their antiproliferative activity against a panel of human tumour cell lines. The key steps of the synthesis represent the initial condensation of suitably protected furanose urononitriles with cysteine ethyl ester hydrochloride, followed by the subsequent oxidation of resulting C-4' epimeric thiazolines with BrCCl3 and DBU, to build up the thiazole ring. Biological studies have shown that the HeLa cell line is most sensitive to the action of synthesized analogues with IC50 values in the range of 0.01-7.67 μM. The most active compound in this cell culture was 7-epi-goniofufurone mimic 28, with a thiazole-carboxamide function at C-7 and a benzyloxy group at the C-5 position. Compound 28 exhibited 89-fold higher antiproliferative potency in this cell line than lead 2 and was 7-fold more active than the commercial antitumour agent doxorubicin. A SAR study identified structural features responsible for the antiproliferative activity of synthesized analogues. The analogues 3-28 are completely inactive toward the normal MRC-5 cell line. Their selectivity indexes (SI) range from 4.1 to 17,470.7.

The study described in the manuscript includes the synthesis of twelve novel hybrid analogues of protulactone A and the evaluation of their antiproliferative activity against a panel of ten tumour and one normal human cell line (foetal lung fibroblasts, MRC-5). The key step in the synthesis was the Grignard addition of PhMgBr to the aldehyde derived from d-galactose, followed by removal of the 1,2-O-isopropylidene protecting group and cyclocondensation of the resulting lactols with Meldrum's acid to build the [3.3.0]furofuranone core. After routine manipulation with present functional groups, the natural product protulactone A and several new hybrid analogues were obtained, ready for biological testing. Several analogues, particularly compounds 9, 13, and 16, showed IC₅₀ values below 10 μM against leukaemia (K562, HL-60), breast (MCF-7, MDA-MB-231), and cervical (HeLa) cancer cells. Selected derivatives (3, 8, 11) further reduced MRP1 levels and induced apoptosis through Caspase-3 activation in K562 cells, indicating their potential as modulators of multidrug resistance. Structure-activity relationship analysis revealed that the introduction of a phenyl group at the C-7 position and specific stereochemical configurations significantly enhanced cytotoxic potency. Importantly, none of the analogues displayed antibacterial or antifungal activity, underscoring their selectivity for tumour cells. Cellular LC-MS/MS profiling revealed that compound 11 achieves uniform high uptake but remains non-toxic to normal cells, demonstrating true pharmacodynamic cancer selectivity. These findings highlight the structural hybridization of protulactone A and styryl lactone as a rational strategy for designing novel anticancer agents with selectivity and relevance in drug resistance contexts.

The first total synthesis and absolute configuration assignment of asperilactone B (I) have been accomplished. Additionally, a revision of the absolute stereochemistry of asperilactone C has been done. The first total synthesis of the opposite enantiomer of asperilactone B (ent-I) has also been achieved, as well as that of C-7 epimers of both asperilactones B (8) and C (9).

Ten new thiophene derivatives related to goniofufurone have been obtained by multistep synthesis starting from D -glucose. The critical step of the synthesis was the Grignard reaction of 2-thienyl magnesium bromide with a protected dialdose, yielding the C-5 epimeric thiophene derivatives 9 and 10 . The mixture was oxidized to the 5keto derivative 11 , which after deprotection was converted to the corresponding keto-lactone 14 . Stereoselective reduction of 14 afforded the thiophene mimic of goniofufurone 3 . Esterification of 3 with cinnamic or 4-fluorocinnamic acid gave hybrids 5 - 7 . Synthesized analogues were evaluated for their in vitro cytotoxicity against several tumour cell lines. The vast majority of them showed better activity than lead 1 . In the culture of K562 cells, compound 3 was more active than the commercial antitumour drug doxorubicin. Structural features of analogues important for their antiproliferative activities were identified by SAR analysis. Pro-apoptotic potential examination of compound 3 on the K562 cell line was performed using flow cytometry, double fluorescence staining and apoptotic morphology screening. Results show that this derivative induces cell membrane disruptions attributable to apoptosis and induces the apoptotic morphology, but decreasing simultaneously the population of cells in the subG1 phase of the cell cycle. The results further suggest that analogue 3 achieves strong cytotoxicity without causing DNA fragmentation. This is clearly indicated by the relatively low incidence of micronuclei, as well as the SAR analysis of all biological effects.

Natural products containing highly oxygenated furanofuranone fragments are known for their potent biological activity, but also for their challenging total synthesis. In this study, the synthesis of five novel dephenylated (-)-goniofufurone analogues was completed and their cytotoxic activity against eight malignant and one normal human cell line was evaluated. Compared with previous syntheses of similar analogues, the synthesis was carried out starting from l -xylose, resulting in improved yields and a reduced number of synthetic steps for three divergent intermediates.

A new total synthesis of the natural S-lactone cleistenolide (1) and its (6S)-stereoisomer 2 was achieved starting from D-glucose. Key steps in the synthesis of 1 involved: oxidative cleavage of the C1-C2 bond in partially protected D-glucose derivative (20), and chain extension of resulting aldehyde 20a with a single C2 fragment using (Z)-selective Wittig olefination. Synthesis of 2 involves the following key steps: periodate cleavage of the C5-C6 bond in the commercially available monoacetone D-glucose (24), followed by C2 chain elongation by using the (Z)-selective Wittig olefination. This new approach is also applied to prepare a few new 4-substituted cleistenolide analogues (3 - 18). Compounds 3 - 7 were designed using molecular hybridization, while the remaining eleven analogues were designed using the bioisosterism method. MTT assay showed that most analogues were more active than lead 1 against several malignant cells, but were completely inactive in the culture of normal foetal lung fibroblasts (MRC-5). The K562 cells appeared to be the most sensitive to the synthesized analogues. The strongest antiproliferative activity against this cell line was shown by 4-O-cinnamoyl derivative 3 and 4,6-di-O-benzyl derivative 17, with submicromolar IC50 values (0.76 and 0.67 mu M, respectively). Structural features important for the activity of this class of compounds were identified by SAR analysis.

A new synthetic approach to protulactone A and several of its structural analogues, starting from d-galactose, has been developed. In a preliminary bioassay, all the compounds showed potent cytotoxicities. A structure–activity relationship analysis identified structural segments that are important for antiproliferative activity.

New thiazole hybrids were synthesized and evaluated for their in vitro cytotoxicity against a panel of human malignant cell lines. The key steps in the synthesis of hybrids 3-7 involved the initial condensation of appropriate aldononitriles with cysteine ethyl ester hydrochloride, followed by subsequent treatment of resulting thiazolines with diazabicycloundecene to form the thiazole ring. Bioisosteres 8 and 14 have been prepared after the stereoselective addition of 2-(trimethylsilyl)thiazole to the hemiacetals obtained by periodate cleavage of terminal diol functionality in the suitably protected d-glucose derivatives. The obtained analogues showed various antiproliferative activities in the cultures of several tumour cell lines. Hybrid 6 was the most potent in HeLa cells, exhibiting more than 10 and 4 times stronger activity than both leads 1 and 2, respectively. The most active compound in Raji cells was hybrid 12, which was nearly 2-fold more potent than the clinical antitumour drug doxorubicin. All analogues were more potent in A549 cells with respect to lead 1, while compounds 6 and 7 were slightly more active than doxorubicin. Preliminary structure-activity relationship analysis revealed that the presence of a cinnamate group at the C-3 position in analogues of type 7 increases the activity of resulting molecular hybrids.

Four novel conformationally restricted (?)-muricatacin analogues, bearing a methoxy group at the C-5 position and with an alkoxymethyl group ?s 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.

(5R)-Cleistenolide and a few related analogues have been synthesized starting from d-glucose. The key steps of the synthesis included a Z-selective Wittig olefination and an intramolecular Mitsunobu reaction with an inversion of configuration at the C-5 position. In vitro antiproliferative activity of synthesized compounds was tested on a panel of eight human tumour cells and against a single normal cell line (MRC-5). The majority of tested compounds showed strong antiproliferative effects on certain human tumour cells and all of them showed negligible toxicity to normal foetal lung fibroblasts (MRC-5). The most active compound obtained in this work is lactone 5, which in MDA-MB 231 cell culture showed the same activity as doxorubicin (IC50 0.09 mu M). Strong antiproliferative activities of analogues 2, 5 and 6 were recorded in the K562 cell line (IC50 0.21, 0.34 and 0.33 mu M, respectively), in which they showed very similar activities to doxorubicin (IC50 0.25 mu M). A performed SAR study revealed that a change in the stereochemistry at the C-5 position may increase the activity of resulting stereoisomers.

Development of a synthetic route applicable to d-ribose and d-xylose enabled the synthesis of cleistanolate putative structure, its five stereoisomers, and led to revision and confirmation of absolute stereochemistry of the natural product. Key steps of the synthesis included zinc-mediated THF ring-opening and stereoselective dihydroxylation under the Upjohn conditions. The first total synthesis of cleistanolate was completed in eight steps starting from d-xylose. The C-5 stereocenter of the natural product was assigned the correct (5S)-stereochemistry. Cytotoxicity of natural product was briefly investigated.

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 (IC50 6.52 and 2.20 mu M, respectively). Some of the synthesized derivatives showed very potent cytotoxicity, especially analogues 11, 13 and 15 (IC50 1.08-1.14 mu M against MCF-7), and 9 and 14 (IC50 1.29 and 1.64 mu M 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.

The synthesis of several new goniofufurone bioisosteres was achieved in which the phenyl residue was replaced by a thiazole ring. The key steps of the synthesis included the initial condensation of cyanohydrin benzoates with cysteine ethyl ester hydrochloride, followed by the subsequent reaction of resulting C-4' epimeric thiazolines with DBU, to introduce 5-deoxy functionality and to elaborate the thiazole ring in one step. Synthesized compounds showed potent growth inhibitory effects against selected human tumour cell lines, especially bioisostere 4, which in the culture of MCF-7 cells displayed the highest activity (IC50 = 0.19 nM) of all compounds under evaluation. This molecule exhibited 64474-fold higher antiproliferative activity than lead 2 and was1053-fold more active than the commercial antitumour agent doxorubicin in the culture of MCF-7 cells. The structural features of the tested compounds responsible for their antiproliferative activity have been identified by preliminary SAR analysis. The toxicity of the most active compound 4 was assessed by an in vivo experiment in a zebrafish model (Danio rerio), whereupon it was found non-toxic at any of the tested concentrations up to 125 μM.

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 delta-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 FeCl3 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 IC50 values of 0.04 (HeLa) and 0.09 mu M (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. (C) 2021 Elsevier Ltd. All rights reserved.

Two natural products, (+)-cardiobutanolide and (-)-3-deoxycardiobutanolide, as well as five new ana-logues, were synthesized in several steps that included zinc-mediated THF ring opening, subsequent stereoselective olefination, and final Sharpless asymmetric dihydroxylation. In vitro antitumour activities of these compounds were evaluated against a panel of eight human tumour cell lines and one normal cell line. Some of compounds displayed powerful effects against tumour cells, but none of them were active toward normal cells. A SAR study revealed that the change of configuration at the C-6 and C-7 position of (+)-cardiobutanolide decreases antitumour activity of analogues. It also appears that the presence of a hydroxyl group at the C-3 position increases the activity of this type of lactones. A comparison of ac-tivities of conformationally rigid lactone goniofufurone with that of more flexible cardiobutanolide and 3-deoxycardiobutanolide indicates that steric flexibility has a positive effect on cytotoxicity. It was also confirmed that removal of the phenyl group may result in analogues of higher activity. Flow cytometry analysis revealed that the synthesized compounds did not induce apoptosis and necrosis of K562 cells. However, Western blot analysis showed that all compounds but one had an increased Bax/Bcl-2 protein expression ratio. (c) 2021 Elsevier Ltd. All rights reserved.