Recent Advances in the Synthesis of α‐Alkylidene‐Substituted δ‐Lactones, γ‐Lactams and δ‐Lactams

Albrecht, Anna; Albrecht, Łukasz; Janecki, Tomasz

doi:10.1002/ejoc.201001486

Cited by 114 publications

(46 citation statements)

References 78 publications

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“…Naturally occurring examples of α-alkylidene-γ-lactams include pukeleimide ( 78 ), possessing an α-methylene group, anatin ( 79 ) with an α-benzylidene group, and gelegamine ( 80 ) possessing an α-ethylidene-δ-lactam (Figure 13). 46 In general, α-methylene lactams are less reactive towards thiols than the corresponding lactones and formation of the thiol adducts usually requires more forcing conditions. 47 For example, α-methylene butyrolactam 81 required thioacetic acid solvent and heating to 50 °C to obtain adduct 82 in 58% yield; 47e for lactams 83 , 84 , and oxindole 87 , thiols were used in excess, and base additives were needed to effect thiol addition in good yields (Scheme 5).…”

Section: αβ-Unsaturated Amides (Acrylamides) and Lactamsmentioning

confidence: 99%

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

et al. 2016

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Although Michael acceptors display a potent and broad spectrum of bioactivity, they have largely been ignored in drug discovery because of their presumed indiscriminate reactivity. As such, a dearth of information exists relevant to the thiol reactivity of natural products and their analogs possessing this moiety. In the midst of recently approved acrylamide-containing drugs, it is clear that a good understanding of the hetero-Michael addition reaction and the relative reactivities of biological thiols with Michael acceptors under physiological conditions is needed for the design and use of these compounds as biological tools and potential therapeutics. This perspective provides information that will contribute to this understanding, such as kinetics of thiol addition reactions, bioactivities, as well as steric and electronic factors that influence the electrophilicity and reversibility of Michael acceptors. This perspective is focused on α,β-unsaturated carbonyls given their preponderance in bioactive natural products.

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Section: αβ-Unsaturated Amides (Acrylamides) and Lactamsmentioning

confidence: 99%

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

et al. 2016

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“…An important, but poorly recognized group of synthetic 2,3‐dihydroquinolin‐4(1 H )‐ones are their 3‐alkylidene(arylidene) derivatives 1 which contain an exo ‐alkylidene(arylidene) bond conjugated with a carbonyl group ( Figure ). This pharmacophoric unit is present in a big group of natural α ‐alkylidene‐ γ ‐ and δ ‐lactones and lactams and is responsible for their biological activity and cytotoxic activity in particular . Consequently, several approaches to 3‐alkylidene(arylidene)‐2,3‐dihydroquinolin‐4‐ones 1 have been reported so far.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 3‐Methylidene‐1‐tosyl‐2,3‐dihydroquinolin‐4(1H)‐ones as Potent Cytotoxic Agents

Koszuk

Bartosik

Wojciechowski

et al. 2018

Chemistry & Biodiversity

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An efficient synthetic strategy to 3-methylidene-2,3-dihydroquinolin-4(1H)-ones variously substituted in position 2 has been developed. The title compounds were synthesized in the reaction sequence involving reaction of diethyl methylphosphonate with methyl 2-(tosylamino)benzoate, condensation of thus formed diethyl 2-oxo-2-(2-N-tosylphenyl)ethylphosphonate with various aldehydes followed by successful application of the obtained 3-(diethoxyphosphoryl)-1,2-dihydroquinolin-4-ols as Horner-Wadsworth-Emmons reagents for the olefination of formaldehyde. Also, enantioselective approach to the target compounds has been evaluated using 3-dimenthoxyphosphoryl group as a chiral auxiliary. Single X-ray crystal analysis of (2S)-3-(dimenthoxyphosphoryl)-2-phenyl-1-tosyldihydroquinolin-4-ol revealed the presence of strong resonance-assisted hydrogen bond (RAHB). The obtained 3-methylidene-2,3-dihydroquinolin-4(1H)-ones were then tested for their cytotoxic activity against two leukemia cell lines NALM-6 and HL-60 and a breast cancer MCF-7 cell line. All compounds showed very high cytotoxic activity with the IC values mostly below 1 μm in all three cancer cell lines. The selected analogs were also tested on human umbilical vein endothelial cells (HUVEC) and on human mammary gland/breast cells (MCF-10A) to evaluate their influence on normal cells. Since one of the most serious problems in cancer chemotherapy is the development of drug resistance, the mRNA levels and activity of ABCB1 transporter considered to be the most important factor engaged in drug resistance, were evaluated in MCF-7 cells treated with two selected analogs. Both compounds were strong ABCB1 transporter inhibitors that could prevent efflux of anticancer drugs from cancer cells.

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“…In contrast to a-methylene-c-lactones (18), a-methylene-dlactones 2 ( Figure 1) are much less abundant in nature and are rarely a target of chemical synthesis (19). The development of new methodologies for the introduction of a methylene group onto the lactone ring enables the straight forward synthesis of a-methylene-d-lactones which may have great potential as lead compounds in further structure-activity relationship studies in the search for new chemotherapeutic agents against cancer.…”

Section: Discussionmentioning

confidence: 97%

Proteomic Analysis of Proteins Engaged in α‐Methylene‐δ‐Lactone Cytotoxic Effects in Hormone‐Independent Breast Cancer MDA‐MB‐231 Cells

et al. 2014

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A simple synthetic α-methylene-δ-lactone, 1-isopropyl-2-methylene-1,2-dihydrobenzochromen-3-one, designated DL-3, was shown previously to induce apoptosis and significantly suppress cell metastatic potential in MDA-MB-231 breast cancer cells. The mechanisms through which DL-3 exerts its effects are poorly understood. The purpose of this study was to investigate the protein expression profiles in MDA-MB-231 cells exposed to the DL-3 treatment. Using 2D differential gel electrophoresis, a set of eight differentially expressed proteins (spot intensities which showed ≥1.25-fold change and statistical significance, p < 0.05, between the control and DL-3-treated group) were found and successfully identified by mass spectrometry (MALDI-TOF/MS). The proteomic results revealed that the presence of DL-3 in MDA-MB-231 cells led to the differential regulation of some proteins that are involved in the cell cycle progression, apoptosis, cytokinesis, modulation of transcription, cellular signaling, and vesicular trafficking. The function of other identified proteins is still unknown. Therefore, our data indicate new directions for the further studies of the pathways engaged in the anticancer action exerted by α-methylene-δ-lactones in cancer cells.

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Recent Advances in the Synthesis of α‐Alkylidene‐Substituted δ‐Lactones, γ‐Lactams and δ‐Lactams

Cited by 114 publications

References 78 publications

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

Synthesis of 3‐Methylidene‐1‐tosyl‐2,3‐dihydroquinolin‐4(1H)‐ones as Potent Cytotoxic Agents

Proteomic Analysis of Proteins Engaged in α‐Methylene‐δ‐Lactone Cytotoxic Effects in Hormone‐Independent Breast Cancer MDA‐MB‐231 Cells

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