- Structure-activity relationships for side chain oxysterol agonists of the hedgehog signaling pathway
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Oxysterols (OHCs) are byproducts of cholesterol oxidation that are known to activate the Hedeghog (Hh) signaling pathway. While OHCs that incorporate hydroxyl groups throughout the scaffold are known, those that act as agonists of Hh signaling primarily contain a single hydroxyl on the alkyl side chain. We sought to further explore how side chain hydroxylation patterns affect oxysterol-mediated Hh activation, by performing a structure-activity relationship study on a series of synthetic OHCs. The most active analogue, 23(R)-OHC (35), demonstrated potent activation of Hh signaling in two Hh-dependent cell lines (EC50 values 0.54-0.65 μM). In addition, OHC 35 was approximately 3-fold selective for the Hh pathway as compared to the liver X receptor, a nuclear receptor that is also activated by endogenous OHCs. Finally, 35 induced osteogenic differentiation and osteoblast formation in cultured cells, indicating functional agonism of the Hh pathway.
- Corman, Audrey,Deberardinis, Albert M.,Hadden, M. Kyle
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Read Online
- An efficient synthesis of the 25-hydroxy Windaus-Grundmann ketone
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A short and efficient synthesis of the 25-hydroxy Windaus-Grundmann ketone from the Inhoffen-Lythgoe diol is described (seven steps, 70% overall). The most relevant feature of the synthesis is the preparation of the Wittig reagent 3 from cheap and commerc
- Fall,Vitale,Mourino
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Read Online
- Discovery of Potential Neuroprotective Agents against Paclitaxel-Induced Peripheral Neuropathy
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Chemotherapy-induced neurotoxicity is a common adverse effect of cancer treatment. No medication has been shown to be effective in the prevention or treatment of chemotherapy-induced neurotoxicity. Using minoxidil as an initial template for structural modifications in conjunction with an in vitro neurite outgrowth assay, an image-based high-content screening platform, and mouse behavior models, an effective neuroprotective agent CN016 was discovered. Our results showed that CN016 could inhibit paclitaxel-induced inflammatory responses and infiltration of immune cells into sensory neurons significantly. Thus, the suppression of proinflammatory factors elucidates, in part, the mechanism of action of CN016 on alleviating paclitaxel-induced peripheral neuropathy. Based on excellent efficacy in improving behavioral functions, high safety profiles (MTD > 500 mg/kg), and a large therapeutic window (MTD/MED > 50) in mice, CN016 might have great potential to become a peripherally neuroprotective agent to prevent neurotoxicity caused by chemotherapeutics as typified by paclitaxel.
- Chang, Jang-Yang,Chen, Chiung-Tong,Chen, Li-Hsien,Chen, Yi-Fan,Chou, Ming-Chen,Lai, Yen-Po,Lee, Chia-Jui,Lee, Hao-Wei,Lee, Jinq-Chyi,Shen, Meng-Ru,Shia, Kak-Shan,Song, Jen-Shin,Wu, Chien-Huang,Wu, Hui-Ling,Yeh, Kai-Chia,Yeh, Teng-Kuang
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supporting information
(2022/03/16)
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- Novel Nonsecosteroidal Vitamin D Receptor Modulator Combined with Gemcitabine Enhances Pancreatic Cancer Therapy through Remodeling of the Tumor Microenvironment
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In a pancreatic tumor microenvironment, activated pancreatic stellate cells (PSCs) produce extracellular matrix (ECM) to form a barrier to drug penetration. Moreover, the interaction between cancer cells and activated PSCs promotes the tumor growth. Vitam
- Kang, Zisheng,Wang, Cong,Tong, Yu,Li, Yanyi,Gao, Yi,Hou, Siyuan,Hao, Meixi,Han, Xiaolin,Wang, Bin,Wang, Qianqian,Zhang, Can
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p. 629 - 643
(2021/02/03)
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- Efficient salt-induced kinase inhibitor and preparation method thereof
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The invention discloses an efficient salt-induced kinase inhibitor and a preparation method thereof, and the efficient salt-induced kinase inhibitor is characterized by comprising substances of a chemical formula in the invention. The salt-induced kinase inhibitor with excellent performance has high inhibitory activity for in-vitro experiments and also has high cell inhibitory activity.
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Paragraph 0136; 0151; 0152
(2021/09/04)
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- Ni-Catalyzed Formal Cross-Electrophile Coupling of Alcohols with Aryl Halides
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Direct coupling of unactivated alcohols remains a challenge in current synthetic chemistry. We herein demonstrate a strategy building upon in situ halogenation/reductive coupling of alcohols with aryl halides to forge Csp2-Csp3 bonds. The combination of 2-chloro-3-ethylbenzo[d]oxazol-3-ium salt (CEBO) and TBAB as the mild bromination reagents enables rapid transformation of a wide range of alcohols to their bromide counterparts within one to 5 min in CH3CN and DMF, which is compatible with the Ni-catalyzed cross-electrophile coupling conditions in the presence of a chemical reductant. The present method is suitable for arylation of a myriad of structurally complex alcohols with no need for prepreparation of alkyl halides. More importantly, the mild and kinetically rapid bromination process has shown good selectivity in the bromination/arylation of symmetric diols and less sterically hindered hydroxyl groups in polyols, thus offering promise for selective functionalization of diols and polyols without laborious protecting/deprotecting operations. The practicality of this work is also evident in the arylation of a number of carbohydrates, drug compounds, and naturally occurring alcohols.
- Lin, Quan,Ma, Guobin,Gong, Hegui
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p. 14102 - 14109
(2021/11/20)
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- Preparation method of a 25-hydroxy vitamin D3 intermediate
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The invention discloses a preparation method of a 25-hydroxy vitamin D3 intermediate, wherein the 25-hydroxy vitamin D3 intermediate is 2-methyl-4-(phenylsulfonyl)-2-butanol, and is prepared from 3-methyl-3-butanol-p-toluenesulfonate, a halide and sodium
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Paragraph 0071-0075; 0079-0083; 0087-0091; 0096-0099
(2020/04/29)
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- Efficient synthesis of 3-TBDMS-11α,25-dihydroxyvitamin D3 and D2 ethers
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Vitamin D deficiency might cause a wide variety of human disorders. As a prerequisite for appropriate diagnosis and therapy, medicinally relevant vitamin D metabolites have to be assayed most accurately and with high specificity. It has been demonstrated, that vitamin D conjugates, linked via a hydroxyl group at C11, might be promising for the development of highly specific antibodies to be employed in competitive protein binding assays. The connective synthesis of 3-TBDMS-11α,25-dihydroxyvitamin D3 and D2 ethers in 500 mg scale, starting from vitamin D2, is described. For installation of a hydroxyl group at C11 a sequence of Pd(OAc)2 mediated oxidation of an enone, epoxidation and subsequent epoxide ring opening was applied to obtain a suitable CD-ring precursor, that was connected with an A-ring diphenylphosphine oxide by Wittig-Horner reaction. Finally, an appropriate side chain was installed, respectively.
- Kattner, Lars,Rauch, Erik
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- CHROMENE DERIVATIVES AS INHIBITORS OF TCR-NCK INTERACTION
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The present invention provides compounds that modulate the interaction of TCR with Nck, compositions thereof, and methods of treatment using the same.
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Paragraph 0444; 0445
(2019/09/06)
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- ISOPROPYL TRIAZOLO PYRIDINE COMPOUNDS
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The present invention provides a compound of the Formula (I) below: Wherein R1 is selected from the group consisting of H, CH3, CN, CH2CN, C(CH3)2CN, and F; R2 is selected from the group consisting of H, O(C1-C3alkyl)R5, CH2CN, and CN; R3 is selected from the group consisting of H, OCH3, CN, C(CH3)2CN, and CH2CN; R4 is selected from the group consisting of H and CH3; R5 is selected from the group consisting of H, CN, C(CH3)2CN, OCH3, S(O)2CH3, and C(CH3)2OH; provided that at least one selected from the group consisting of R1, R2, R3 and R4 is H; or a pharmaceutically acceptable salt thereof, methods of treating diabetes using the compound and a process for preparing the compound.
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Paragraph 0074-0075
(2016/12/01)
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- PROTEIN KINASE INHIBITORS
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A compound of formula (I), wherein R3, R4, G, B, M, and Z are as defined in the claims, and pharmaceutically acceptable salts thereof are disclosed. The compounds of formula (I) possess utility as FGFR inhibitors and are useful in the treatment of a condition, where FGFR kinase inhibition is desired, such as cancer.
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Paragraph 0138
(2015/02/18)
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- PHENYL-TRIAZOLO-PYRIDINE COMPOUNDS
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The present invention provides a compound of the Formula (I) below: wherein R1 is selected from the group consisting of H, CH3, CN, -CH2CN, -C(CH3)2CN, F, Cl, and Br; R2 is selected from the group consisting of H, -O(C1-C3alkylene)R4, -CH2CN, CN, - OCH3, CF2, -C(CH3)2CN, -C(CH3)2, -S(O)2CH3, -S(O)2NH2, and -OCF2; R3 is selected from the group consisting of H, CH3, and -OCH3; and R4 is selected from the group consisting of H, -C(CH3)2CN, -OCH3, -S(O)2CH3, CN, and -C(CH3)2OH; or a pharmaceutical salt thereof, methods of treating type two diabetes using the compound and a process for preparing the compound.
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Page/Page column 13; 14
(2015/07/23)
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- TRITERPENOIDS WITH HIV MATURATION INHIBITORY ACTIVITY, SUBSTITUTED IN POSITION 3 BY A NON-AROMATIC RING CARRYING A HALOALKYL SUBSTITUENT
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Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, triterpenoids that possess unique antiviral activity are provided as HIV maturation inhibitors, as represented by compounds of Formula I: with X selected from C4-8 cycloalkyl, C4-8 cycloalkenyl, C4-9 spirocycloalkyl, C4-9 spirocycloalkenyl, C4-8 oxacycloalkyl, C4-8 dioxacycloalkyl, C6-8 oxacycloalkenyl, C6-8 dioxacycloalkenyl, C6 cyclodialkenyl, C6 oxacyclodialkenyl, C6-9 oxaspirocycloalkyl and C6-9 oxaspirocycloalkenyl ring, such that X is substituted with A, wherein A is -C1-6 alkyl- halo. These compounds are useful for the treatment of HIV and AIDS.
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Page/Page column 185; 186
(2015/11/03)
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- SUBSTITUTED XANTHINES AND METHODS OF USE THEREOF
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Compounds, compositions and methods are described for inhibiting the TRPC5 ion channel and disorders related to TRPC5.
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Page/Page column 403
(2014/09/29)
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- PROTEIN KINASE INHIBITORS
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A compound of formula (I), wherein R3, R4, G, B, M, and Z are as defined in the claims, and pharmaceutically acceptable salts thereof are disclosed. The compounds of formula (I) possess utility as FGFR inhibitors and are useful in the treatment of a condition, where FGFR kinase inhibition is desired, such as cancer.
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Page/Page column 32
(2013/04/25)
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- INDOLE BASED RECEPTOR CRTH2 ANTAGONISTS
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Disclosed are compounds of Formula (I): which are useful as antagonists of the CRTH2 receptors. Pharmaceutical compositions containing compounds of Formula (I) and the use of compounds of Formula (I) to treat diseases or disorders that are responsive to inhibition of the binding of endogenous ligands to the CRTH2 receptor are also disclosed. Methods for preparing and using these compounds are further described.
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Page/Page column 51
(2011/05/08)
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- Substituted N-aryl heterocycles, process for their preparation and their use as medicaments
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The invention relates to substituted N-aryl heterocycles and to the physiologically tolerated salts and physiologically functional derivatives thereof. Compounds of the formula I in which the radicals have the stated meanings, the N-oxides and the physiologically tolerated salts thereof and process for the preparation thereof are described. The compounds are suitable for example as anorectic agents.
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- Highly potent cell differentiation-inducing analogues of 1α,25-dihydroxyvitamin D3: Synthesis and biological activity of 2-methyl-1,25-dihydroxyvitamin D3 with side-chain modifications
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Eight 2-methyl substituted analogues of 20-epi-22R-methyl-1α,25-dihydroxyvitamin D3 (5) and 20-epi-24,26,27-trihomo-22-oxa-1α,25-dihydroxyvitamin D3 (6: KH-1060) were convergently synthesized. Preparation of the CD-ring portions with modified side chains of 5 and 6, followed by palladium-catalyzed cross-coupling with the A-ring enyne synthons (20a-d), (3S,4S,5R)-, (3S,4R,5R)-, (3S,4S,5S)- and (3R,4R,5S)-3,5-bis[(tert-butyldimethylsilyl)oxy]-4-methyloct-1-en-7-yne, afforded two sets of four A-ring stereoisomers of 20-epi-2,22-dimethyl-1,25-dihydroxyvitamin D3 (7a-d) and 20-epi-24,26,27-trihomo-2-methyl-22-oxa-1,25-dihydroxyvitamin D3 (8a-d). The biological profiles of the hybrid analogues were assessed in terms of affinity for vitamin D receptor (VDR) and HL-60 cell differentiation-inducing activity in comparison with the natural hormone. The combined modifications of the A-ring at the 2-position and the side chain yielded analogues with high potency.
- Fujishima, Toshie,Zhaopeng, Liu,Konno, Katsuhiro,Nakagawa, Kimie,Okano, Toshio,Yamaguchi, Kentaro,Takayama, Hiroaki
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p. 525 - 535
(2007/10/03)
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- Vitamin D analogues
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STR1 The present invention relates to compounds of formula (I), in which formula, n is 0 or 1, m is 0 or an integer from 1-7, R1 and R2 (which may be the same or different) stand for hydrogen or C1 l-C8 -hydroca
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- Competition between two metabolic pathways: oxidation and desulfuration in the thiobarbiturate series
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In order to study the competition between hepatic hydroxylation and desulfuration in the thiobarbiturate series, two compounds bearing a branched side chain with a tertiary carbon atom in position ω-1 were administered to rats over about one week.Urine and faeces were collected and extracted.The metabolites isolated were identified.It was shown that desulfuration was not the major metabolic pathway, and that, when it took place, it remained a minor process and was accompanied by γ-hydroxylation into a tertiary alcohol. thiobarbiturate series / metabolism / oxidation / desulfuration
- Yebga, A.,Menager, S.,Verite, P.,Farnoux, C. Combet,Lafont, O.
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p. 769 - 778
(2007/10/03)
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- Vitamin D3 analogs
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Compounds of the formula STR1 wherein R is hydrogen or hydroxy, R5 is hydrogen, and A is --C C--, STR2 or --CH2 --CH2 --, with the proviso that when A is --C C--, R5 may also be deuterium, are described. The compounds of formula I are useful as agents for the treatment of hyperproliferative disorders of the skin such as psoriasis, as agents for the treatment of neoplastic diseases such as leukemia, and as agents for the treatment of sebaceous gland diseases such as acne or seborrheic dermatitis.
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- AN EFFICIENT ROUTE TO 1α,25-DIHYDROXYVITAMIN D3 FUNCTIONALIZED AT C-11
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An efficient route to vitamin D3 analogues functionalized at C-11 is described.Key features of this synthesis are: (i) the development of a novel and efficient route for the introduction of the 25-hydroxylated side chain, present in the most im
- Torneiro, Mercedes,Fall, Yagamare,Castedo, Luis,Mourino, Antonio
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p. 105 - 108
(2007/10/02)
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- RHODIUM CARBENOID MEDIATED CYCLISATIONS. PART 2. SYNTHESIS OF CYCLIC ETHERS
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Alkylation of the dianion of methyl acetoacetate with the t-butyldimethylsilyl protected α,ω-halogeno alcohols (1)-(9) gives the β-keto esters (1) which are converted into the diazo alcohols (3) by diazo transfer and desilylation.Rhodium carbenoid cyclisa
- Heslin, Julie C.,Moody, Christopher J.
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p. 1417 - 1424
(2007/10/02)
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- Reactions of Methyl Radicals with 3-Methyloxetane, 3,3-Dimethyloxetane and 2,2-Dimethyloxetane
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The reactions of methyl radicals with 3-methyloxetane, 3,3-dimethyloxetane and 2,2-dimethyloxetane have been studied.The overall rates of hydrogen-atom abstraction from these three compounds have been obtained over the temperature range 100-200 deg C by assuming the value of Quinn and coworkers (J.Chem.Soc.Faraday Trans.I, 1976, 72, 1935) for the rate of recombination of methyl radicals.The following rate expressions were found: log10(k4/cm3mol-1s-1)(30x) = 11.69 (+/-0.20)-38.23 (+/-0.84) kJmol-1/2.303RT, log10(k4/cm3mol-1s-1)(3,30x) = 11.72 (+/-0.20)-39.47 (+/-1.0) kJmol-1/2.303RT, log10(k4/cm3mol-1s-1)(2,20x) = 11.99 (+/-0.23)-41.24 (+/-1.13) kJmol-1/2.303RT.From these rate expressions and those obtained previously for three other oxetane molecules, the rate parameters for hydrogen-atom abstraction from five distinct sites in the substituted oxetane molecules have been obtained.
- Duke, Martin G.,Holbrook, Kenneth A.
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p. 3391 - 3398
(2007/10/02)
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