72311-12-7Relevant academic research and scientific papers
Substituted dienes prepared from betulinic acid – Synthesis, cytotoxicity, mechanism of action, and pharmacological parameters
Frydrych, Ivo,Urban, Milan,?arek, Jan,Benická, Sandra,D?ubák, Petr,Gurská, Soňa,Hajdúch, Marián,Kotulová, Jana,Li?ková, Barbora,Olejníková, Denisa,Pokorny, Jan
, (2021/07/28)
A set of new substituted dienes were synthesized from betulinic acid by its oxidation to 30-oxobetulinic acid followed by the Wittig reaction. Cytotoxicity of all compounds was tested in vitro in eight cancer cell lines and two noncancer fibroblasts. Almost all dienes were more cytotoxic than betulinic acid. Compounds 4.22, 4.30, 4.33, 4.39 had IC50 below 5 μmol/L; 4.22 and 4.39 were selected for studies of the mechanism of action. Cell cycle analysis revealed an increase in the number of apoptotic cells at 5 × IC50 concentration, where activation of irreversible changes leading to cell death can be expected. Both 4.22 and 4.39 led to the accumulation of cells in the G0/G1 phase with partial inhibition of DNA/RNA synthesis at 1 × IC50 and almost complete inhibition at 5 × IC50. Interestingly, compound 4.39 at 5 × IC50 caused the accumulation of cells in the S phase. Higher concentrations of tested drugs probably inhibit more off-targets than lower concentrations. Mechanisms disrupting cellular metabolism can induce the accumulation of cells in the S phase. Both compounds 4.22 and 4.39 trigger selective apoptosis in cancer cells via intrinsic pathway, which we have demonstrated by changes in the expression of the crucial apoptosis-related protein. Pharmacological parameters of derivative 4.22 were superior to 4.39, therefore 4.22 was the finally selected candidate for the development of anticancer drug.
Global PROTAC Toolbox for Degrading BCR-ABL Overcomes Drug-Resistant Mutants and Adverse Effects
Yang, Yiqing,Gao, Hongying,Sun, Xiuyun,Sun, Yonghui,Qiu, Yueping,Weng, Qinjie,Rao, Yu
, p. 8567 - 8583 (2020/09/16)
The BCR-ABL fusion oncoprotein causes chronic myeloid leukemia or acute lymphoblastic leukemia in Ph+ patients because the ABL kinase is constitutively activated. However, current clinical treatment with ABL inhibitors is seriously limited by drug resistance and adverse effects. Although the emerging proteolysis-Targeting chimeras (PROTACs) have been introduced to degrade BCR-ABL, most of them showed limited activity and could not overcome the common drug-resistant mutants, especially for T315I mutant. Herein, we systematically designed a set of unique PROTACs by globally targeting all the three binding sites of BCR-ABL, including dasatinib-, ponatinib-, and asciminib-based PROTACs. Our ponatinib-based PROTACs showed practical activity as dasatinib-based PROTACs, while no reported ponatinib-based PROTACs could degrade BCR-ABL before. As a proof of concept, some additional dasatinib-based PROTACs were then designed to degrade T315I mutant too. We provided a global PROTAC toolbox for degrading both wild-Type and T315I-mutated BCR-ABL from each binding site. More importantly, these PROTACs showed better selectivity and less adverse effects than the inhibitors, indicating that PROTACs had great potential for overcoming clinical drug resistance and safety issues.
Synthesis of Seco-Analogues of the DHCR24 Inhibitor SH-42
Bracher, Franz,Heerdegen, Desirée,Kornmayer, Moritz M.,Kriegler, Katharina N.,Müller, Christoph,Mayer, Peter,Reuter, Doreen
, p. 6270 - 6288 (2020/10/02)
In a project aimed at the further development of the potent steroidal anti-inflammatory Δ24-dehydrocholesterol reductase (DHCR24) inhibitor SH-42 we worked out routes to ring B seco-steroidal analogues. The required building blocks, bearing rings C and D of the parent steroidal structure, were synthesised starting from ergocalciferol. The novel seco-analogues carry aromatic residues as ring A equivalents at C-4 position with variation of the linker length resulting in 4-aryl-, 4-benzyl- and 4-(arylethyl)perhydroindanes. As saturated analogues of the latter 4-(cyclohexylethyl)perhydroindanes were prepared. Moreover, aromatic and aliphatic residues were attached to C-5 position of the perhydroindane scaffold. Unfortunately, none of these structurally diverse seco-analogues of SH-42 showed noteworthy inhibition of target enzyme DHCR24, indicating the relevance of the intact steroidal structure for the development of potent inhibitors of this enzyme.
MULTIVALENT RAS BINDING COMPOUNDS
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Paragraph 00812, (2017/07/23)
Described herein are compounds that modulate Ras signaling, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with altered Ras signaling. Further described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds and methods of using such compounds in the treatment of cell proliferative disorders, including cancer.
Synthesis and anti-inflammatory activity of phenylbutenoid dimer analogs
Kim, Sung-Soo,Fang, Yuanying,Park, Haeil
, p. 1676 - 1680 (2015/07/15)
Several phenylbutenoid dimer (PBD) analogs were synthesized and evaluated for their inhibitory activities against nitric oxide (NO) production and TNF-α release. The PBD analogs were synthesized via Diels - Alder and subsequent Schlosser reactions as key steps. Among the tested compounds, two analogs (8c, 8f) exhibited much stronger inhibitory activity against LPS-stimulated NO production and TNF-α release in RAW 264.7 cells than that of wogonin.
One-pot synthesis of gem-difluorostyrenes from benzyl bromide via olefination of phosphonium ylide with difluorocarbene
Deng, Xiao-Yun,Lin, Jin-Hong,Xiao, Ji-Chang
, p. 116 - 120 (2015/11/10)
A new approach for the synthesis of gem-difluorostyrenes from benzyl bromide is described. Quaternization of triphenylphosphine with benzyl bromide to give phosphonium salts, deprotonation of the corresponding phosphonium salts to produce phosphonium ylide, and the subsequent olefination of phosphonium ylide with difluorocarbene generated from difluoromethylene phosphobetaine (Ph3P+CF2CO2-) by decarboxylation can occur smoothly in one-pot, furnishing the final gem-difluorostyrenes in good yields.
Synthesis of combretastatin A4 analogues on steroidal framework and their anti-breast cancer activity
Parihar, Swati,Kumar, Amit,Chaturvedi, Amit K.,Sachan, Naresh Kumar,Luqman, Suaib,Changkija, Bendangla,Manohar, Murli,Prakash, Om,Chanda,Khan, Feroz,Chanotiya,Shanker, Karuna,Dwivedi, Anila,Konwar, Rituraj,Negi, Arvind S.
, p. 332 - 344 (2013/11/19)
Combretastatin A4 analogues were synthesized on steroidal framework from gallic acid with a possibility of anti-breast cancer agents. Twenty two analogues were synthesized and evaluated for cytotoxicity against human breast cancer cell lines (MCF-7 & MDA-MB 231). The best analogue 22 showed potent antitubulin effect. Docking experiments also supported strong binding affinity of 22 to microtubule polymerase. In cell cycle analysis, 22 induced apoptosis in MCF-7 cells significantly. It was found to be non-toxic up to 300 mg/kg dose in Swiss albino mice in acute oral toxicity. This article is part of a Special Issue entitled "Synthesis and biological testing of steroid derivatives as inhibitors".
Design, synthesis, in vitro cytotoxicity evaluation and structure-activity relationship of Goniothalamin analogs
Mohideen, Mazlin,Zulkepli, Suraya,Nik-Salleh, Nik-Salmah,Zulkefeli, Mohd,Weber, Jean-Frédéric Faizal Abdullah,Rahman, A. F. M. Motiur
, p. 812 - 831 (2013/07/26)
A series of six/five member (E/Z)-Goniothalamin analogs were synthesized from commercially available (3,4-dihydro-2H-pyran-2-yl)methanol/5- (hydroxymethyl)dihydrofuran-2(3H)-one in three steps with good to moderate overall yields and their cytotoxicity against lymphoblastic leukemic T cell line (Jurkat E6.1) have been evaluated. Among the synthesized analogs, (Z)-Goniothalamin appeared to be the most active in cytotoxicity (IC 50 = 12 μM). Structure-activity relationship study indicates that introducing substituent in phenyl ring or replacing phenyl ring by pyridine/naphthalene, or decreasing the ring size of lactones (from six to five member) do not increase the cytotoxicity.
Design of living ring-opening alkyne metathesis
Fischer, Felix R.,Nuckolls, Colin
supporting information; experimental part, p. 7257 - 7260 (2010/11/05)
It's alive: A ring-strained alkyne based on dibenzo[a,e][8]annulene undergoes ringopening metathesis polymerization (ROMP) to give a high-molecular-weight poly(ortho-phenylene) featuring alternating ethyl and ethynyl linkers along the polymer backbone. The molybdenumalkylidyne- based catalyst system discriminates between strained and unstrained alkynes to yield a living polymer with an unparalleled low polydispersity.
Separation of α-glucosidase-inhibitory and liver X receptor-antagonistic activities of phenethylphenyl phthalimide analogs and generation of LXRα-selective antagonists
Motoshima, Kazunori,Noguchi-Yachide, Tomomi,Sugita, Kazuyuki,Hashimoto, Yuichi,Ishikawa, Minoru
experimental part, p. 5001 - 5014 (2009/12/24)
Liver X receptor (LXR) α/β dual agonists are candidate medicaments for the treatment of metabolic syndrome, because their biological actions include increasing cholesterol efflux mediated by LXRβ. However, their clinical application is currently limited by their enhancing effect on triglyceride (TG) synthesis mediated by LXRα. Combination of an LXRα-selective antagonist with an LXRα/β dual agonist may overcome this disadvantage. In the present work, structural development studies of phenethylphenyl phthalimide 9, which possesses LXRα/β dual-antagonistic activity and α-glucosidase-inhibitory activity, led to the LXRα-selective antagonist 23f. Specific α-glucosidase inhibitors were also obtained.
