- Discovery of novel dihydroartemisinin-cinnamic hybrids inducing lung cancer cells apoptosis via inhibition of Akt/Bad signal pathway
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A series of dihydroartemisinin-cinnamic acid hybrids were designed, synthesized and evaluated. Most of the tested compounds showed enhanced anti-proliferative activities than artemisinin and dihydroartemisinin, among which 16 g had the superior potency with IC50 values ranging from 5.07 μM to 7.88 μM against four tested cancer cell lines. The cell cycle arrest revealed that 16 g induced A549 cell cycle arrest at G0/G1 phase via regulation of G1-related protein expression (Cdk4). Further mechanism studies reveal that 16 g induced A549 cells apoptosis via inhibiting Akt/Bad pathway. Moreover, 16 g depolarized the mitochondria membrane potentials and induced ROS generation in A549. Additionally, 16 g blocked migration of A549 cells in a concentration-dependent manner. What's more, 16 g is barely nontoxic to zebrafish embryos. Overall, the cell cycle arrest, inhibition of Akt/Bad signal pathway, ROS generation and migration blocked might explain the potent anti-proliferative activities of these compounds.
- Hu, Yanping,Wang, Yujin,Li, Na,Chen, Li,Sun, Jianbo
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- trans-Selective hydrocyanation of ynoates, ynones and ynoic acids catalyzed by nucleophilic phosphines
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trans-Selective hydrocyanation of ynoates and ynones in the presence of TMSCN and an alcohol additive are catalyzed by nucleophilic phosphines. The trisubstituted E-olefin products of anti-addition of hydrogen cyanide to the alkyne are produced with high regio- and stereoselectivity. The alcohol additive reacts with TMSCN to produce hydrogen cyanide in situ. Ynoic acids undergo the phosphine catalyzed hydrocyanation in the presence of TMSCN under aprotic conditions only. In these reactions, TMSCN reacts with the acid to generate hydrogen cyanide and the silyl ester which, unlike the acid, undergoes phosphine catalyzed hydrocyanation and gives the stereo-defined E-2-cyano-acrylic acids after work up.
- Meyer, Maximilian,Peri?, Milica,Sch?mberg, Fritz,Vilotijevi?, Ivan
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supporting information
(2021/10/04)
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- Development of Novel Mitochondrial Pyruvate Carrier Inhibitors to Treat Hair Loss
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Herein, we report the synthesis and evaluation of novel analogues of UK-5099 both in vitro and in vivo for the development of mitochondrial pyruvate carrier (MPC) inhibitors to treat hair loss. A comprehensive understanding of the structure-activity relationship was obtained by varying four positions of the hit compound, namely, the alkyl group on the N1 position, substituents on the indole core, various aromatic and heteroaromatic core structures, and various Michael acceptors. The major discovery was that the inhibitors with a 3,5-bis(trifluoromethyl)benzyl group at the N1 position were shown to have much better activity than JXL001 (UK-5099) to increase cellular lactate production. Additionally, analogue JXL069, possessing a 7-azaindole heterocycle, was also shown to have significant MPC inhibition activity, which further increases the chemical space for drug design. Finally, more than 10 analogues were tested on shaved mice by topical treatment and promoted obvious hair growth on mice.
- Liu, Xiaoguang,Flores, Aimee A.,Situ, Lisa,Gu, Wen,Ding, Hui,Christofk, Heather R.,Lowry, William E.,Jung, Michael E.
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p. 2046 - 2063
(2021/02/16)
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- COMPOSITIONS AND METHODS FOR MODULATING HAIR GROWTH
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The present disclosure relates to compounds that are capable of inhibiting the mitochondrial pyruvate carrier and promoting hair growth. The disclosure further relates to methods of promoting hair growth or treating conditions or disorders affecting hair growth, such as baldness or alopecia.
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Page/Page column 78-79
(2020/07/21)
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- Discovery of Novel Celastrol Derivatives as Hsp90-Cdc37 Interaction Disruptors with Antitumor Activity
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To develop novel and efficient heat shock protein 90-cell division cycle 37 (Hsp90-Cdc37) interaction disruptors, several lipophilic fragments were introduced into celastrol (CEL) to synthesize 48 new CEL derivatives. Among all the target compounds, 41 wa
- Li, Na,Xu, Manyi,Wang, Bing,Shi, Zhixian,Zhao, Zihao,Tang, Yunqing,Wang, Xinyue,Sun, Jianbo,Chen, Li
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p. 10798 - 10815
(2019/12/25)
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- Development of the First Two-Pore Domain Potassium Channel TWIK-Related K+ Channel 1-Selective Agonist Possessing in Vivo Antinociceptive Activity
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The TWIK-related K+ channel, TREK-1, has recently emerged as an attractive therapeutic target for the development of a novel class of analgesic drugs, suggesting that activation of TREK-1 could result in pain inhibition. Here, we report the synthesis of a series of substituted acrylic acids (1-54) based on our previous work with caffeate esters. The analogues were evaluated for their ability to modulate TREK-1 channel by electrophysiology and for their in vivo antinociceptive activity (acetic acid-induced writhing and hot plate assays), leading to the identification of a series of novel molecules able to activate TREK-1 and displaying potent antinociceptive activity in vivo. Furyl analogue 36 is the most promising of the series.
- Vivier, Delphine,Soussia, Ismail Ben,Rodrigues, Nuno,Lolignier, Stéphane,Devilliers, Ma?ly,Chatelain, Franck C.,Prival, Laetitia,Chapuy, Eric,Bourdier, Geoffrey,Bennis, Khalil,Lesage, Florian,Eschalier, Alain,Busserolles, Jér?me,Ducki, Sylvie
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supporting information
p. 1076 - 1088
(2017/02/19)
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- Monocarboxylate transporter 1 inhibitors as potential anticancer agents
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Potent monocarboxylate transporter 1 inhibitors (MCT1) have been developed based on α-cyano-4-hydroxycinnamic acid template. Structure-activity relationship studies demonstrate that the introduction of p-N, N-dialkyl/diaryl, and o-methoxy groups into cyanocinnamic acid has maximal MCT1 inhibitory activity. Systemic toxicity studies in healthy ICR mice with few potent MCT1 inhibitors indicate normal body weight gains in treated animals. In vivo tumor growth inhibition studies in colorectal adenocarcinoma (WiDr cell line) in nude mice xenograft models establish that compound 27 exhibits single agent activity in inhibiting the tumor growth.
- Gurrapu, Shirisha,Jonnalagadda, Sravan K.,Alam, Mohammad A.,Nelson, Grady L.,Sneve, Mary G.,Drewes, Lester R.,Mereddy, Venkatram R.
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p. 558 - 561
(2015/05/27)
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- CINNAMIC ACID AMIDE DERIVATIVE
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The present invention provides a cinnamic acid amide derivative having an excellent analgesic action. The cinnamic acid amide derivative of the present invention is a compound showing excellent analgesic actions to not only a nociceptive pain model animal but also a neuropathic pain model animal, which is very useful as an agent for treating various pain diseases showing acute or chronic pains or neuropathic pains.
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Paragraph 0104
(2015/11/24)
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- Base catalyzed formation and ring cleavage of 2- acyl-4- alkoxycarbonyl- 4-cyano substituted cyclohexanoles
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THE REACTION of 1,3-diaryl-2-propen-1-ones (1a,b) with ethyl cyanoacetate in absolute ethanol in the presence of a catalytic amount of KOH at 50-55 °C afforded 3-aroyl-1-cyano-4-hydroxy-2,4, 6-triarylcyclohexanecarboxylates (2a,b). Base-catalyzed ring cleavage of 2a,b in refluxing ethanolic KOH solution afforded the corresponding 3-aryl- 2-cyano-2-propenoic acid 4 along with 1a,b. The structure of 2 was established through different spectroscopic techniques and confirmed via dehydration using thionyl chloride in refluxing pyridine afforded 3. However, reaction of 1a with ethyl cyanoacetate in refluxing ethanol in the presence of secondary amine (piperidine or morpholine) as a basic catalyst gave the open-chain Michael adduct 6. Treatment of the latter with ethanolic KOH solution yielded 1,5-pentanedione derivative 7. The relative configurations of 3b and 6 were determined through single crystal X-ray diffraction analysis.
- Mishriky,Girgis,Ahmed-Farag
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experimental part
p. 249 - 264
(2012/04/23)
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- Reaction of active methylene compounds with 4-fluorobenzalanilines and antifungal potential of the products
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Condensation of active methylene compounds (1-6) with 4-fluorobenzalaniline resulted in the formation of addition-elimination products 1a-6a respectively. The products were identified on the basis of elemental analysis, m.m.p. determination and spectral studies and were screened in vitro for their antifungal potential against four phytopathogenic fungi.
- Sandhar, Randeep Kaur,Sharma,Manrao
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p. 263 - 265
(2007/10/03)
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- Cosmetic composition
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A composition suitable for topical application to mammalian skin and hair for inducing, maintaining or increasing hair growth comprises a hair growth promoter chosen from glutamine derivatives and salts thereof. The composition preferably also comprises an activity enhancer which may be chosen from hair growth stimulants, penetration enhancers and cationic polymers.
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- Cosmetic composition containing DOPA derivatives
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A composition for topical application to human hair or skin contains a chemical analogue of dihydroxyphenyl alanine (DOPA). This chemical analogue can be absorbed by skin or by a hair follicle and metabolised in-vivo, thus leading to the formation of melanin in skin or to the growth of melanin-pigmented hair. Consequently the composition can give controlled skin darkening to mimic sun-induced tanning or can bring about the growth of dar hair in place of the grey or white hair.
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- Cosmestic composition
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A composition suitable for topical application to mammalian skin and hair for inducing, maintaining or increasing hair growth comprises a hair growth promoter chosen from glutamic acid derivatives and salts thereof. The composition preferably also comprises an activity enhancer which may be chosen from hair growth stimulants, penetration enhancers and cationic polymers.
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- Tyrphostins I: Synthesis and Biological Activity of Protein Tyrosine Kinase Inhibitors
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A novel class of low molecular weight proteine kinase inhibitors is described.These compounds consitute a systematic series of molecules with a progressive increase in affinity toward the substrate site of the EGF receptor kinase domain.These competitive inhibitors also effectively block the EGF-dependent autophosphorylation of the receptor.The potent EGF receptor kinase blockers examined were found to competitively inhibit the homologous insulin receptor kinase at 102-103 higher inhibitor concentrations in spite of the significant homology between these protein tyrosine kinases.These results demonstrate the ability to synthesize selective tyrosine kinase inhibitors.The most potent EGF receptor kinase inhibitors also inhibit the EGF-dependent proliferation of A431/clone 15 cells with little or no effect on EGF independent cell growth.These results demonstrate the potential use of protein tyrosine kinase inhibitors as selective antiproliferative agents for proliferative diseases caused by the hyperactivity of protein tyrosine kinases.We have suggested the name "tyrphostins" for this class of antiproliferative compounds which act as protein tyrosine kinase blockers.
- Gazit, Aviv,Yaish, Pnina,Gilon, Chaim,Levitzki, Alexander
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p. 2344 - 2352
(2007/10/02)
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- Transmiision of substituent effects through extended systems II. Substituted cis and trans cinnamonitriles
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Infrared data and 13C chemical shifts are reported for a series of p-substituted cis and m-substituted trans cinnamonitriles.The i.r. values include intensities for the benzene, ethylene and cyanide vibrations which allow an estimation of resonance effect
- Butt, G.,Topsom, R. D.
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p. 301 - 306
(2007/10/02)
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