共查询到20条相似文献,搜索用时 9 毫秒
1.
Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents 总被引:5,自引:0,他引:5
Adams BK Ferstl EM Davis MC Herold M Kurtkaya S Camalier RF Hollingshead MG Kaur G Sausville EA Rickles FR Snyder JP Liotta DC Shoji M 《Bioorganic & medicinal chemistry》2004,12(14):3871-3883
A series of novel curcumin analogs were synthesized and screened for anti-cancer and anti-angiogenesis activities at Emory University and at the National Cancer Institute (NCI). These compounds are symmetrical alpha,beta-unsaturated and saturated ketones. The majority of the analogs demonstrated a moderate degree of anti-cancer activity. Compounds 10, 11, and 14 exhibited a high degree of cytotoxicity in the NCI in vitro anti-cancer cell line screen. In addition, this screen revealed that these compounds inhibit tumor cell growth with a higher potency than the commonly used chemotherapeutic drug, cisplatin. In independent in vitro screens conducted at Emory, the same compounds plus 4, 5, 8, 9, and 13 exhibited a high degree of cytotoxicity to tumor cells. Analogs that were effective in the anti-cancer screens were also effective in in vitro anti-angiogenesis assays. Compounds 4, 9, 11, and 14 were most effective in the anti-angiogenesis assays run at Emory. In the assays conducted by the NCI, compound 14 was almost as potent as the anti-angiogenic drug TNP-470, which has undergone clinical trials. Based on the favorable in vitro anti-cancer and anti-angiogenesis results with 14, further in vivo tests were conducted. This compound effectively reduced the size of human breast tumors grown in female athymic nude mice and showed little toxicity. This data, coupled with the remarkable in vitro data, suggests that compound 14 may potentially be an effective chemotherapeutic agent. As a follow-up, a 3D quantitative structure relationship based on 14 has been developed. It shows a cross-validated r2(q2) and a predictive r2(p2) = 0.71. COMPARE analysis suggests the compound to be a possible RNA/DNA antimetabolite, but also implies that the compound's cytotoxicity may arise from a presently unknown mechanism. 相似文献
2.
David Y.W. Lee Lu Yang Wei Xu Gang Deng Lin Guo Lee-Yuan Liu-Chen 《Bioorganic & medicinal chemistry letters》2010,20(19):5749-5752
Salvinorin A (1), the main active ingredient of Salvia divinorum, is a potent and selective κ opioid receptor (KOPR) agonist. Based on the SAR, its C-2 position is one of the key binding sites and has very little space tolerance (3–4 carbons atoms) and limited to only lipophilic groups. In our attempt to prepare PET brain imaging agent for mapping KOPR, a series of C-2 halogenated analogs have been synthesized and screened for binding affinity at κ (KOPR), μ (MOPR), and δ (DOPR). These C-2 halogenated analogs with sequential changes of atomic radius and electron density serve as excellent molecular probes for further investigating the binding pocket at C-2, particularly on the effects of α verses β configuration at C-2 position. The results of KOPR binding and functional studies reveal β isomer in general binds better than α isomer with the exception of iodinated analogs and none of the C-2 halogenated analogs shows any improvement of KOPR binding affinity. Interestingly, functional assay has characterized that 6b is a partial agonist with Emax of 46% of the kappa receptor full agonist U50,488H at 250 nM (Ki). We have also observed that the affinity to the kappa receptor increases with atomic radius (I > Br > Cl > F) which is in good agreement with halogen bonding interactions reported in the literature. 相似文献
3.
Jaeschke G Porter R Büttelmann B Ceccarelli SM Guba W Kuhn B Kolczewski S Huwyler J Mutel V Peters JU Ballard T Prinssen E Vieira E Wichmann J Spooren W 《Bioorganic & medicinal chemistry letters》2007,17(5):1307-1311
Optimization of affinity and microsomal stability led to identification of the potent, metabolically stable fenobam analog 4l. Robust in vivo efficacy of 4l was demonstrated in four different models of anxiety. Additionally, a ligand based pharmacophore alignment of fenobam and MPEP is proposed. 相似文献
4.
Zunhua Yang Yuanying Fang Tuan-Anh N. Pham Jongkook Lee Haeil Park 《Bioorganic & medicinal chemistry letters》2013,23(5):1519-1521
5-Nitropyrimidine analogs substituted with conformationally restricted azabicyclic amines and alcohols were prepared and evaluated their agonistic activity against human GPR119. The analogs bearing endo-azabicyclic amines and alcohols (7, 8, 11, and 12) exhibited full agonistic activities while the analogs with exo-azabicyclic amines and alcohols were proved as partial agonists (9, 10, 13, and 14) regardless of their EC50 values. 5-Nitropyrimidine analogs with (2-fluoro-4-methylsulfonyl)phenylamino group (8, 10, 12, 14) showed more potent GPR119 activation activities than the analogs without fluorine in all cases (7, 9, 11, 13). 相似文献
5.
6.
《Bioorganic & medicinal chemistry letters》2014,24(16):4023-4025
Recent studies suggest that arylhydrocarbon receptor (AhR) may be a target for a number of diseases. Natural product malassezin is a AhR agonist with an interesting 2,3′-diindolylmethane skeleton. We have prepared a series of analogues of natural product malassezin using our recently developed method and tested the activity of these analogues against AhR in a cell-based assay. We found that a methyl substituent at 1′-N can significantly increase the activity and the 2-formyl group is not critical for some diindolylmethanes. 相似文献
7.
Franchetti P Cappellacci L Pasqualini M Grifantini M Lorenzi T Raffaelli N Magni G 《Nucleosides, nucleotides & nucleic acids》2003,22(5-8):865-868
Two dinucleoside polyphosphate NAD analogs, P1-(adenosine-5')-P3-(nicotinamide riboside-5')triphosphate (Np3A, 1) and P1-(adenosine-5')-P4-(nicotinamide riboside-5')tetraphosphate (Np4A, 2), were synthesized and tested as inhibitors of both microbial and human recombinant NMN adenylyltransferase. Compounds 1 and 2 proved to be selective inhibitors of microbial enzymes. 相似文献
8.
Rose JD Maddry JA Comber RN Suling WJ Wilson LN Reynolds RC 《Carbohydrate research》2002,337(2):105-120
Analogs of trehalose are reported that were designed to interfere with mycolylation pathways in the mycobacterial cell wall. Several derivatives of 6,6'-dideoxytrehalose, including N,N'-dialkylamino and 6,6'-bis(sulfonamido) analogs, were prepared and evaluated for antimycobacterial activity against Mycobacterium tuberculosis H(37)Ra and a panel of clinical isolates of Mycobacterium avium. 6,6'-Diaminotrehalose and its diazido precursor were both inactive, but significant activity apparently related to aliphatic chain length was found among the sulfonamides, N-alkylamines, and one of the amidines. 相似文献
9.
Wang X Bhatia PA Daanen JF Latsaw SP Rohde J Kolasa T Hakeem AA Matulenko MA Nakane M Uchic ME Miller LN Chang R Moreland RB Brioni JD Stewart AO 《Bioorganic & medicinal chemistry》2005,13(15):4667-4678
A series of 3-aryl piperidine analogs with 2-piperidinoalkylamino or 2-piperidinoalkyloxy fused bicyclic rings were prepared and found to be potent and efficacious human dopamine D4 agonists. The synthesis and structure-activity relationship (SAR) studies that led to the identification of these compounds are discussed. 相似文献
10.
Shaikha S. AlNeyadi Abdu Adem Naheed Amer Alaa A. Salem Ibrahim M. Abdou 《Bioorganic & medicinal chemistry letters》2017,27(22):5071-5075
The therapeutic success of peptide glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus has inspired discovery efforts aimed at developing orally available small-molecule GLP-1 receptor agonists. In this study, two series of new pyrimidine derivatives were designed and synthesized using an efficient route, and were evaluated in terms of GLP-1 receptor agonist activity. In the first series, novel pyrimidines substituted at positions 2 and 4 with groups varying in size and electronic properties were synthesized in a good yield (78–90%). In the second series, the designed pyrimidine templates included both urea and Schiff base linkers, and these compounds were successfully produced with yields of 77–84%. In vitro experiments with cultured cells showed that compounds 3a and 10a (10?15–10?9 M) significantly increased insulin secretion compared to that of the control cells in both the absence and presence of 2.8 mM glucose; compound 8b only demonstrated significance in the absence of glucose. These findings represent a valuable starting point for the design and discovery of small-molecule GLP-1 receptor agonists that can be administered orally. 相似文献
11.
《International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology》1990,17(4):347-356
Three 18F-labeled benzamide derivatives were prepared and evaluated as potential ligands to study the dopamine D2 receptor phenomenon. The compounds are analogs of iodobenzamide, eticlopride and raclopride and are labeled with an N-2-[18F]fluoroethyl functionality on the pyrrolidine ring. The compounds were tested in vitro for binding affinity and found to exhibit somewhat lower affinity than the non-fluorinated analog. In vivo distribution studies revealed that all compounds were more highly bound to plasma proteins than was raclopride. In addition, compartmentation of radioactivity demonstrated nonspecific binding to be the predominate retention in the brain as reflected by the low caudate to cerebellum ratios for these compounds. These three 18F-labeled benzamide derivatives are inferior to raclopride and iodobenzamide for studies of the D2 receptor system using positron emission tomography. 相似文献
12.
It is thought that selective 5-HT(4) receptor agonists-such as 4-amino-5-chloro-2-methoxy-N-[1-(6-oxo-6-phenylhexyl)piperidin-4ylmethyl]benzamide (2)-have the ability to enhance both upper and lower gastrointestinal motility without any significant adverse effects. Modification of 2 was performed. Variation of the piperidin-4ylmethyl moiety of 2 led to a decrease in the binding affinity for the 5-HT(4) receptor. Following conversion of the carbonyl group on the benzoyl part to a hydroxyl or sulfoxide group, the binding affinity for the 5-HT(4) receptor was retained although the effect on defecation was reduced. Many of the 4-amino-5-chloro-2-methoxy-N-(piperidin-4ylmethyl)benzamides that had a ether or sulfide moiety in the side-chain part at the 1-position of the piperidine exhibited high affinity for the 5-HT(4) receptor. Among these, phenylthio 41c and benzylthio derivative 44 were selective 5-HT(4) receptor agonists, and had a similar effect on defecation to compound 2. 相似文献
13.
Qiu X Liu Z Shao WY Liu X Jing DP Yu YJ An LK Huang SL Bu XZ Huang ZS Gu LQ 《Bioorganic & medicinal chemistry》2008,16(17):8035-8041
Series of curcumin derivatives were synthesized; the inhibitory activities on thioredoxin reductase (TrxR) of all analogues were evaluated by DTNB assay in vitro. It is found that most of the analogues can inhibit TrxR in the low micromolar range; Structure-activity relationship analysis reveals that analogues with furan moiety have excellent inhibitory effect on TrxR in an irreversible manner, indicating that the furan moiety may serve as a possible pharmacophore during the interaction of curcumin analogues with TrxR. The effect of selected curcuminoids on growth of different TrxR overexpressed cancer cell lines was also investigated and discussed. 相似文献
14.
Synthesis and biological evaluation of [D-lysine]8cyclosporin A analogs as potential anti-HCV agents
Scribner A Houck D Huang Z Mosier S Peel M Scorneaux B 《Bioorganic & medicinal chemistry letters》2010,20(22):6542-6546
An efficient synthesis of [D-lysine](8)cyclosporin A has been developed. Several analogs of [D-lysine](8)cyclosporin A have been synthesized and show promising anti-HCV activity, particularly compounds 39 and 43, which each exhibit an anti-HCV EC(50)<200 nM, and are each ≥50-fold less immunosuppressive than cyclosporin A. 相似文献
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16.
《Bioorganic & medicinal chemistry letters》2014,24(17):4281-4285
A series of thienopyrimidine derivatives was synthesized and evaluated for their GPR119 agonistic ability. Several thienopyrimidine derivatives containing R1 and R2 substituents displayed potent GPR119 agonistic activity. Among them, compound 5d, which is a prototype, showed good in vitro activity with an EC50 value of 3 nM and human and rat liver microsomal stability. Compound 5d exhibited no CYP inhibition and induction, Herg binding, or mutagenic potential. Compound 5d showed increase insulin secretion in beta TC-6 cell and lowered the glucose excursion in mice in an oral glucose-tolerance test. 相似文献
17.
Hong C. Shen Fa-Xiang Ding Sheo B. Singh Gopalakrishnan Parthasarathy Stephen M. Soisson Sookhee N. Ha Xun Chen Srinivas Kodali Jun Wang Karen Dorso James R. Tata Milton L. Hammond Malcolm MacCoss Steven L. Colletti 《Bioorganic & medicinal chemistry letters》2009,19(6):1623-1627
Platensimycin (1) displays antibacterial activity due to its inhibition of the elongation condensing enzyme (FabF), a novel mode of action that could potentially lead to a breakthrough in developing a new generation of antibiotics. The medicinal chemistry efforts were focused on the modification of the enone moiety of platensimycin and several analogs showed significant activity against FabF and possess antibacterial activity. 相似文献
18.
Hyojin Kim Suk Joon Cho Minjin Yoo Seung Kyu Kang Kwang Rok Kim Hwan Hee Lee Jin Sook Song Sang Dal Rhee Won Hoon Jung Jin Hee Ahn Jae-Kyung Jung Kwan-Young Jung 《Bioorganic & medicinal chemistry letters》2017,27(23):5213-5220
A series of 4-(phenoxymethyl)thiazole derivatives was synthesized and evaluated for their GPR119 agonistic effect. Several 4-(phenoxymethyl)thiazoles with pyrrolidine-2,5-dione moieties showed potent GPR119 agonistic activities. Among them, compound 27 and 32d showed good in vitro activity with an EC50 value of 49?nM and 18?nM, respectively with improved human and rat liver microsomal stability compare with MBX-2982. Compound 27 & 32d did not exhibit significant CYP inhibition, hERG binding, and cytotoxicity. Moreover, these compounds lowered the glucose excursion in mice in an oral glucose-tolerance test. 相似文献
19.
John S. Debenham Christina B. Madsen-Duggan Junying Wang Xinchun Tong Julie Lao Tung M. Fong Marie-Therese Schaeffer Jing Chen Xiao Cathy C.R.-R. Huang Chun-Pyn Shen D. Sloan Stribling Lauren P. Shearman Alison M. Strack D. Euan MacIntyre Jeffrey J. Hale Thomas F. Walsh 《Bioorganic & medicinal chemistry letters》2009,19(9):2591-2594
The synthesis, SAR and binding affinities are described for cannabinoid-1 receptor (CB1R) specific inverse agonists based on pyridopyrimidine and heterotricyclic scaffolds. Food intake and pharmacokinetic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R. 相似文献
20.
Foss FW Snyder AH Davis MD Rouse M Okusa MD Lynch KR Macdonald TL 《Bioorganic & medicinal chemistry》2007,15(2):663-677
The synthesis of N-arylamide phosphonates and related arylether and arylamine analogues provided potent, subtype-selective agonists and antagonists of the five known sphingosine 1-phosphate (S1P) receptors (S1P(1-5)). To this end, the syntheses of phosphoserine mimetics-selectively protected and optically active phosphonoserines-are described. In vitro binding assays showed that the implementation of phosphonates as phosphate mimetics provided compounds with similar receptor binding affinities as compared to their phosphate precursors. meta-substituted arylamide phosphonates were discovered to be antagonists of the S1P(1) and S1P(3) receptors. When administered to mice, an antagonist blocked the lymphopenia evoked by a S1P receptor agonist and caused capillary leakage in both lung and kidney. 相似文献