Identification of Gli-mediated transcription inhibitors through synthesis and evaluation of taepeenin D analogues

Antoniou, Antonia I.; Chatzopoulou, Maria; Bantzi, Marina; Athanassopoulos, Constantinos M.; Giannis, Athanassios; Pitsinos, Emmanuel N.

doi:10.1039/c6md00354k

Cited by 10 publications

(9 citation statements)

References 28 publications

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“…From this initial SAR data analysis, it could be deduced that the methyl group at the C-14 positions of this family of compounds is not always crucial for their cytotoxic activity. This conjecture agrees with the results of a study by Pitsinos et al [ 5 , 6 ].…”

Section: Resultssupporting

confidence: 94%

“…Researchers have reported only a few syntheses of these interesting diterpenoids due to their relatively complex structures. In this sense, Pitsinos et al reported the synthesis of 14-desmethyl taepeenin D ( 2 ) and a series of second-generation analogs of taepeenin D ( 1 ) with the aim of investigating their structure–activity relationship ( SAR ) [ 5 ]. These authors argued that the presence of the methyl group in C-14 does not influence the anticancer activity of this type of compound [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Biological Evaluation of Cassane Diterpene (5α)-Vuacapane-8(14), 9(11)-Diene and of Some Related Compounds

et al. 2022

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A set of thirteen cassane-type diterpenes was synthesized and an expedient synthetic route was used to evaluate 14-desmethyl analogs of the most active tested cassane. The anti-inflammatory activities of these 13 compounds were evaluated on a lipopolysaccharide (LPS)-activated RAW 264.7 cell line by inhibition of nitric oxide (NO) production, some of them reaching 100% NO inhibition after 72 h of treatment. The greatest anti-inflammatory effect was observed for compounds 16 and 20 with an IC50 NO of 2.98 ± 0.04 μg/mL and 5.71 ± 0.14 μg/mL, respectively. Flow-cytometry analysis was used to determine the cell cycle distribution and showed that the inhibition in NO release was accompanied by a reversion of the differentiation processes. Moreover, the anti-cancer potential of these 13 compounds were evaluated in three tumor cell lines (B16-F10, HT29, and Hep G2). The strongest cytotoxic effect was achieved by salicylaldehyde 20, and pterolobirin G (6), with IC50 values around 3 μg/mL in HT29 cells, with total apoptosis rates 80% at IC80 concentrations, producing a significant cell-cycle arrest in the G0/G1 phase, and a possible activation of the extrinsic apoptotic pathway. Additionally, initial SAR data analysis showed that the methyl group at the C-14 positions of cassane diterpenoids is not always important for their cytotoxic and anti-inflammatory activities.

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Section: Resultssupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Cassane Diterpene (5α)-Vuacapane-8(14), 9(11)-Diene and of Some Related Compounds

et al. 2022

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“…The proposed DHA-chalcone hybrids ( Scheme 1 ) were synthesized from the readily available DHA ( 1 ), which was easily transformed to the C13 acetyl 28 and formyl 30 derivatives the based on experimental procedures described previously [ 34 ]. Cross-aldol condensation of 27 or 28 with arylaldehydes in the presence of barium hydroxide octahydrate gave the corresponding hybrid compounds 31 – 47 , where the DHA’s aromatic ring coincides with the chalcone “A” ring [ 36 ].…”

Section: Resultsmentioning

confidence: 99%

“…In connection to our previous studies where we used dehydroabietic acid as a chiral template to prepare either anticancer [ 34 ] or antimicrobial agents [ 35 ] and considering the potential of a chalcone pharmacophore, we thought it of interest to synthesize a series of hybrid DHA-chalcone molecules (suitable for structure–activity relationship studies) and to evaluate them for their antiproliferative activity against three breast cancer cell lines (MCF-7, MDA-MB-231, and Hs578T). The synthetic methodology is described below and involves two key intermediates derived from DHA, the DHA C13 ketone 28 and the DHA C13 aldehyde 30 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antiproliferative Activity of Novel Dehydroabietic Acid-Chalcone Hybrids

et al. 2022

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Dehydroabietic Acid (DHA, 1) derivatives are known for their antiproliferative properties, among others. In the context of this work, DHA was initially modified to two key intermediates bearing a C18 methyl ester, a phenol moiety at C12, and an acetyl or formyl group at C13 position. These derivatives allowed us to synthesize a series of DHA-chalcone hybrids, suitable for structure–activity relationship studies (SARS), following their condensation with a variety of aryl-aldehydes and methyl ketones. The antiproliferative evaluation of the synthesized DHA-chalcone hybrids against three breast cancer cell lines (the estrogen-dependent MCF-7 and the estrogen-independent MDA-MB-231 and Hs578T) showed that eight derivatives (33, 35, 37, 38, 39, 41, 43, 44) exhibit low micromolar activity levels (IC50 2.21–11.5 μΜ/MCF-7). For instance, some of them showed better activity compared to the commercial anticancer drug 5-FU against MCF-7 cells (33, 41, 43, 44) and against MDA-MB231 (33 and 41). Hybrid 38 is a promising lead compound for the treatment of MCF-7 breast cancer, exhibiting comparable activity to 5-FU and being 12.9 times less toxic (SI = 22.7). Thus, our findings suggest that DHA-chalcone hybrids are drug candidates worth pursuing for further development in the search for novel breast cancer therapies.

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“…The procedures leading to the target DHAA derivatives are depicted in Figure 1 and are based on previous experience using DHAA as precursor for the synthesis of a series of taepeenin D analogs [39]. Starting from compound 1, the corresponding methyl ester 2 was obtained and was further used without purification for a Friedel-Crafts acylation reaction to afford the C-12 ketone 3.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Structure–Activity Relationships of Novel Abietane Diterpenoids with Activity against Staphylococcus Aureus

et al. 2019

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Aim: To find alternative compounds against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus (MSSA), novel derivatives from dehydroabietic acid were synthesized. Methods & results: Compound 12 was the most effective against 15 MRSA and 11 MSSA with minimum inhibitory concentration values ranging from 3.9 to 15.6 μg/ml. Although less active than 12, compound 11, followed by 25 and 13, also exhibited anti-staphylococcal activity. Additional studies showed that compound 12 is devoid of toxic effect on non-target cells. A structure–activity relationship study revealed that an oxime at C-13 together with a hydroxyl at C-12 could play a key role in the activity. Conclusion: These structures, in particular compound 12, could arise as templates for the development of agents against MRSA and MSSA.

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Identification of Gli-mediated transcription inhibitors through synthesis and evaluation of taepeenin D analogues

Abstract: Abietic acid derivatives related to taepeenin D were identified as new Hh pathway inhibitors that operate downstream of Smo.

Cited by 10 publications

References 28 publications

Synthesis and Biological Evaluation of Cassane Diterpene (5α)-Vuacapane-8(14), 9(11)-Diene and of Some Related Compounds

Synthesis and Biological Evaluation of Cassane Diterpene (5α)-Vuacapane-8(14), 9(11)-Diene and of Some Related Compounds

Synthesis and Antiproliferative Activity of Novel Dehydroabietic Acid-Chalcone Hybrids

Synthesis and Structure–Activity Relationships of Novel Abietane Diterpenoids with Activity against Staphylococcus Aureus

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