The application of tandem aza-wittig reaction to synthesize artemisinin-guanidine hybrids and their anti-tumor activity

Three series of novel artemisinin–guanidine hybrids 4a–4f , 8a–8h and 9a–9h have been facilely synthesized via four‐component reaction (aza‐Wittig reaction) and evaluated for their anti‐tumor activities against A549, HT‐29 and MDA‐MB‐231 cell lines in vitro. All of the tested compounds showed enhanced anti‐tumor activities with IC₅₀ values ranging from 0.02 µM to 12.0 µM as compared to DHA (dihydroartemisinin). Among them, artemisinin derived dimers, compounds 9b (IC₅₀ = 0.05 µM), 9d (IC₅₀ = 0.06 µM) and 9f (IC₅₀ = 0.02 µM) were found to be most active against HT29 cells.     

Anti-tumor activity of new artemisinin-chalcone hybrids

In an attempt to develop potent and selective anti‐tumor agents, three new series of artemisinin–chalcone hybrids 10a – 10g , 11a – 11g and 12a–12h were designed, synthesized and screened for their anti‐tumor activity against five cell lines (HT‐29, A549, MDA‐MB‐231, HeLa and H460) in vitro. Among compounds 10a–g and 11a–11g , most of them displayed enhanced activity and good selectivity toward HT‐29 and HeLa cell lines with IC₅₀ values ranging from 0.12 to 0.85 µM as compared with DHA (dihydroartemisinin). Compounds 10a and 11a are most active toward HeLa cells with IC₅₀ values of 0.12 and 0.19 µM. The results revealed that the presence of chalcone moiety is beneficial to their activity and selectivity. In addition, compounds 12a ‐ 12h containing a ‘reversed chalcone’ moiety showed only slight improvement in activity than those of DHA.     

Synthesis and Biological Evaluation of Oxygen‐containing Heterocyclic Ring‐fused 23‐Hydroxybetulinic Acid Derivatives as Antitumor Agents

A collection of isoxazole and oxadiazole substituted 23‐hydroxybetulinic acid (HBA) derivatives were designed, synthesized and evaluated for their antitumor activity. Most of the newly synthesized compounds exhibited more potent antiproliferative activity than patent compound 23‐hydroxybetulinic acid, especially 13e and 14a were about four‐ to sevenfold more potent against all tested cancer cell lines than 23‐hydroxybetulinic acid. Furthermore, the in vivo antitumor activity of 13e and 14a was validated in H22 liver cancer and B16 melanoma xenograft mouse models. The structure–activity relationships of these 23‐hydroxybetulinic acid derivatives were also discussed based on the present investigation.     

Synthesis and Biological Evaluation of 4‐Arylphthalazones Bearing Benzenesulfonamide as Anti‐Inflammatory and Anti‐Cancer Agents

Nine 4‐arylphthalazones bearing benzenesulfonamide (2a – i ) were synthesized by the condensation of the appropriate 2‐aroylbenzoic acid ( 1a – i ) and 4‐hydrazinobenzenesulfonamide in ethanol. The structures of these compounds were elucidated by elemental analysis, IR, ¹H NMR, ¹³C NMR, and MS spectroscopy. Two compounds, 2b and 2i , showed significant anti‐inflammatory activity comparable to that of the standard drug celecoxib in the carrageenan‐induced rat paw edema model. These compounds ( 2b and 2i ) had selective inhibitory activity towards the COX‐2 enzyme. Compound 2b had a better selectivity ratio (COX‐1/COX‐2) compared to that of celecoxib and can be used as a novel template for the design of selective COX‐2 inhibitors. Compounds 2d and 2i were screened for their antiproliferative activity toward 60 human cancer cell lines by the National Cancer Institute (USA). The compounds 2d and 2i displayed mild activity toward the renal cancer cell line UO‐31.     

Synthesis and Evaluation of Novel 2‐Substituted‐quinazolin‐4(3H)‐ones as Potent Analgesic and Anti‐inflammatory Agents

A novel series of 2‐substituted‐quinazolin‐4(3H)‐ones were synthesized by reacting 3,5‐disubstituted‐anthranilic acid with acetic anhydride/benzoyl chloride, which were further reacted with different primary amines to obtain 2,6,8‐substituted‐quinazolin‐4(3H)‐ones 6a–f , 7 , 8 . All the synthesized compounds were characterized and screened for analgesic and anti‐inflammatory activities. Compounds 6,8‐dibromo‐2‐phenyl‐3‐(4′‐carboxyl phenyl)quinazolin‐4(3H)‐one 7 and 6,8‐dibromo‐2‐phenyl‐3‐(2′‐phenylethanoic acid)quinazolin‐4(3H)‐one 8 displayed good analgesic and anti‐inflammatory activity in comparison to the reference standards acetyl salicylic acid and indomethacin, respectively.     

Comparison of in vitro cytotoxicity,estrogenicity and anti‐estrogenicity of triclosan,perfluorooctane sulfonate and perfluorooctanoic acid

Concern with increasing levels of emerging contaminants exists on a global scale. Three commonly observed emerging environmental contaminants: triclosan (2,4,4‐trichloro‐2′‐hydroxydiphenyl ether), a synthetic, broad‐spectrum antibacterial agent, and perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), used in stain‐ and water‐resistant treatments, have become distributed ubiquitously across ecosystems and have been detected in wildlife and humans. MCF‐7 BOS human breast cancer cells were used to investigate the potential for cytotoxicity, estrogenicity and anti‐estrogenicity of these three compounds at environmentally relevant concentrations using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium, inner salt assay (MTS) and the E‐SCREEN bioassay. The doses used were 0.002–200 µg ml^?1 for triclosan and 0.03–30 µg ml^?1 for PFOS and PFOA. Quantitative results from the MTS assay revealed no significant cytotoxicity at lower concentrations for any of the test compounds; however, both triclosan and PFOA were cytotoxic at the highest concentrations examined (100–200 and 30 µg ml^?1, respectively), while PFOS showed no significant cytotoxicity at any of the concentrations tested. Positive estrogenic responses (P < 0.05) were elicited from the E‐SCREEN at all concentrations examined for triclosan and PFOA and at 30 µg ml^?1 for PFOS. Further, significant anti‐estrogenic activity (P < 0.05) was detected for all compounds tested at all concentrations when cells were co‐exposed with 10^?9 m 17‐β estradiol (E₂). The overall results demonstrated that triclosan, PFOS and PFOA have estrogenic activities and that co‐exposure to contaminants and E₂ produced anti‐estrogenic effects. Each of these compounds could provide a source of xenoestrogens to humans and wildlife in the environment. Published 2011. This article is a US Government work and is in the public domain in the USA.     

Design and Synthesis of 2‐Phenoxynicotinic Acid Hydrazides as Anti‐inflammatory and Analgesic Agents

A series of 2‐phenoxynicotinic acid hydrazides were synthesized and evaluated for their analgesic and anti‐inflammatory activities. Several compounds having an unsubstituted phenyl/4‐pyridyl or C‐4 methoxy substituent on the terminal phenyl ring showed moderate to high analgesic or anti‐inflammatory activity in comparison to mefenamic acid as the reference drug. The compounds with highest anti‐inflammatory activity were subjected to in vitro COX‐1/COX‐2 inhibition assays and showed moderate to good COX‐1 and weak COX‐2 inhibition activities.     

Synthesis and Structure‐Activity Relationship Studies of Pyrazole‐based Heterocycles as Antitumor Agents

Several 4‐cyano‐1,5‐diphenylpyrazoles attached to different heterocyclic ring systems at position 3 were synthesized starting from ethyl 4‐cyano‐1,5‐diphenyl‐1H‐pyrazole‐3‐carboxylate 1 . The newly synthesized compounds were tested in vivo for their anti‐estrogenic effects and evaluated in vitro for their cytotoxic properties against estrogen‐dependent tumors. 3‐(5‐Mercapto‐1,3,4‐oxadiazole‐2‐yl)‐1,5‐diphenyl‐1H‐pyrazole‐4‐carbonitrile 13 revealed the highest cytotoxic activity with a GI₅₀ value equal to 40 nM against the IGROVI ovarian tumor cell line. It also showed an anti‐estrogen activity 1.6 more effective than the reference drug, in addition to a high tolerable dose. 3‐(5‐(Methylthio)‐4‐phenyl‐4H‐1,2,4‐triazol‐3‐yl)‐1,5‐diphenyl‐1H‐pyrazole‐4‐carbonitrile 7 was found to have the highest anti‐estrogenic activity, while 1,5‐diphenyl‐3‐[5‐(phenylamino)‐1,3,4‐thiadiazol‐2‐yl]‐1H‐pyrazole‐4‐carbonitrile 11 showed the lowest activity. The oral LD₅₀ values revealed that most of the tested compounds are relatively nontoxic.     

Novel Side‐Chain Glucosylated and Adamantylated [Asp2/Glu2]Enkephalin Analogs: Synthesis and In Vitro Growth Inhibition of Human Tumor Cells

A series of new backbone‐modified Leu‐ and Met‐enkephalin analogs ( 13 – 20 a and b ) were synthesized. Backbone manipulations involved the replacement of the Gly² residue in Tyr‐Gly‐Gly‐Phe‐Leu/Met with side‐chain glucosylated or adamantylated D /L ‐aspartic or ‐glutamic acids. The in vitro antiproliferative activity of these compounds was evaluated for several cell lines and the results were compared with the effect of Met‐enkephalin, the native opioid growth factor. The tested compounds modestly inhibited the growth of the tumor cells (20–50% inhibition at millimolar concentrations). Among the tested compounds, Tyr‐D ‐Glu(AdNH)‐Gly‐Phe‐Met ( 20b ) showed significant antiproliferative activity, somewhat more pronounced on MCF‐7 (breast carcinoma) and MOLT‐4 (lymphoblastic leukemia) cells.     

Relative inhibitory activity of bile acids against 12‐O‐tetradecanoylphorbol‐13‐acetate‐induced inflammation,and chenodeoxycholic acid inhibition of tumour promotion in mouse skin two‐stage carcinogenesis

Objectives Bile acids are present in Bezoar Bovis and Fel Ursi, traditionally used as antipyretics and antispasmodics. However the anti‐inflammatory activity of individual bile acids and related compounds has not yet been investigated. In this paper, we report the structure–activity relationships influencing the anti‐inflammatory activity of a variety of structurally different bile acid derivatives and also the inhibitory activity of chenodeoxy‐cholic acid against tumour promotion. Methods Fifty derivatives of bile acids were examined for their inhibitory activity against the induction of oedema in mouse ear by application of 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA). Also, the effect of chenodeoxycholic acid was studied in mouse skin in which tumours had been induced by topical application of 7,12‐dimethylbenz[a]anthracene (DMBA) and promoted by TPA. Key findings Many bile acid derivatives had an inhibitory effect against TPA‐induced ear oedema at a similar grade to that of indometacin. Chenodeoxycholic acid, methyl 3α,7α,15α‐trihydroxy‐5β‐cholan‐24‐oate and methyl 3α,7α,15β‐trihydroxy‐5β‐cholan‐24‐oate showed the most potent activity with an ID50 value of 71–110 nmol/ear, a level corresponding to that of hydrocortisone (69 nmol/ear). Furthermore, chenodeoxycholic acid markedly suppressed tumour‐promoting activity by TPA following initiation by DMBA in mouse skin. Conclusions This is the first report on the anti‐inflammatory activity of bile acids on TPA‐induced inflammatory ear oedema in mice. Chenodeoxycholic acid, methyl 3α,7α,15α‐trihydroxy‐5β‐cholan‐24‐oate and methyl 3α,7α,15β‐trihydroxy‐5β‐cholan‐24‐oate showed the most potent activity, at a level corresponding to that of hydrocortisone. Furthermore, chenodeoxycholic acid markedly inhibited tumour promotion in a two‐stage carcinogenesis model in mouse skin.     

Synthesis and biological activities of 2-amino-thiazole-5-carboxylic acid phenylamide derivatives

In an attempt to develop potent and selective anti‐tumor drugs, a series of novel 2‐amino‐thiazole‐5‐carboxylic acid phenylamide derivatives were designed based on the structure of dasatinib. All compounds were synthesized by a systematic combinatorial chemical approach. Biological evaluation revealed that N‐(2‐chloro‐6‐methylphenyl)‐2‐(2‐(4‐methylpiperazin‐1‐yl)acetamido)thiazole‐5‐carboxamide ( 6d ) exhibited high antiproliferative potency on human K563 leukemia cells comparable to dasatinib. Against mammary and colon carcinoma cells 6d was either inactive (MDA‐MB 231) or distinctly less active (MCF‐7 and HT‐29: IC₅₀ = 20.2 and 21.6 µM, respectively). Dasatinib showed at each cell line IC₅₀ < 1 µM. The results of this structure activity relationship study clearly documented that the pyrimidin‐4‐ylamino core of dasatinib is responsible for the anti‐tumor activity against non‐leukemia cell lines.     

Synthesis and elastase inhibition activities of novel aryl,substituted aryl,and heteroaryl oxime ester derivatives

Fifteen novel aryl, substituted aryl and heteroaryl γ‐hydroxy‐ ( 2a–e ), γ‐methoxyimin o‐ (3a–e ), and γ‐benzyloxyimino‐ ( 4a–e ) butyric acid methyl esters were investigated for their enzyme inhibition, and the synthesis of 10 compounds ( 3a–e , 4a–e ) is given in this study. The other five compounds ( 2a–e ) were synthesized before in another study. Compounds 3a–e and 4a–e were synthesized in this work as original compounds and characterized by ¹H and ¹³C NMR, IR, mass, and elemental analyses. Their (E/Z)‐isomerisation ratios were analyzed by ¹H and ¹³C NMR. All of them are of pure (E)‐configuration. Due to the literature survey, the elastase inhibition activity was not studied for these compounds. Elastase inhibition ability was investigated in this work for five γ‐hydroxy‐ ( 2a–e ), five γ‐methoxy‐ ( 3a–e ), and five γ‐benzyloxyimino‐ ( 4a–e ) butyric acid methyl esters. All these 15 compounds showed elastase inhibition activity. Compound 2b was the best one and exhibited a better activity than the standard ursolic acid whereas compound 2a worked like the standard. All these compounds can be novel elastase inhibitor agents in the pharmaceutical and cosmetic industries.

     

Anti‐inflammatory and anticancer compounds isolated from Ventilago madraspatana Gaertn., Rubia cordifolia Linn. and Lantana camara Linn.

Objectives The aim was to search for anti‐inflammatory and anticancer compounds from three medicinal plants, viz. Ventilago madraspatana Gaertn., Rubia cordifolia Linn. and Lantana camara Linn. Methods The NO? scavenging potential of selected plant extracts was determined on LPS/IFN‐γ activated murine peritoneal macrophage cultures, and iNOS and COX‐2 expression was evaluated by Western blot analysis. Bio‐assay guided fractionation yielded four compounds: physcion and emodin from V. madraspatana, 1‐hydroxytectoquinone from R. cordifolia, and oleanonic acid from L. camara. The anti‐inflammatory activity of these compounds was tested through the carrageenan‐induced rat‐paw oedema model. They were then tested against a murine tumour (Ehrlich ascites carcinoma), and three human cancer cell lines, namely A375 (malignant skin melanoma), Hep2 (epidermoid laryngeal carcinoma) and U937 (lymphoma). Key findings All four compounds dose dependently inhibited NO? through suppression of iNOS protein without affecting macrophage viability. Physcion and emodin caused 65–68% reduction of oedema volume at 40 mg/kg, which validated their in‐vivo anti‐inflammatory effect. 1‐hydroxytectoquinone and oleanonic acid exhibited promising cytotoxicity against A375 cells. Conclusions Ethnomedical reports on these traditional medicinal plants have been rationalised through an insight into the anti‐inflammatory as well as anticancer potential of four constituents, characterised to be prospective candidates for designing novel therapeutic agents.     

Synthesis and 3D‐QSAR Analysis of 2‐Chloroquinoline Derivatives as H37RV MTB Inhibitors

Frequency of tuberculosis is progressively increasing worldwide. New emerging strains of bacilli that are emerging are resistant to the currently available drugs which make this issue more alarming. In this regard, a series of substituted quinolinyl chalcones, quinolinyl pyrimidines, and pyridines were synthesized and evaluated for their antitubercular activity in vitro against Mycobacterium tuberculosis H₃₇RV. To establish the role of the 2‐chloroquinoline nucleus as a pharmacophoric group and study its influence on the antimycobacterial activity, a 3D‐QSAR study based on CoMFA and CoMSIA was undertaken on this set of 2‐chloroquinoline derivatives. Statistically significant models that are able to well correlate the antimycobacterial activity with the chemical structures of the 2‐chloroquinolines have been developed. The contour maps resulting from the best CoMFA and CoMSIA models were used to identify the structural features relevant to the biological activity in this series of analogs. Further analysis of these interaction‐field contour maps also showed a high level of internal consistency. The information obtained from the field 3‐D contour maps may be fruitfully utilized in the design of more potent 2‐chloroquinoline‐based analogs as potential antitubercular candidates.     

Cytotoxic and trypanocidal activities of cinchona alkaloid derivatives

A series of 27 cinchona alkaloid derivatives ( 1f–w , 2a–e and 3a–d ) were investigated for their cytotoxic and trypanocidal activities using seven different cancer cell lines (KB, HeLa, MCF‐7, A‐549, Hep‐G2, U‐87 and HL‐60), two normal cell lines (HDF and CHO) and bloodstream forms of Trypanosoma brucei brucei, respectively. Four compounds ( 1u , 1w , 2e and 3d ) were identified with promising cytotoxic activity with 50% growth inhibition (GI₅₀) values below 10 μM. Two ( 2e and 3d ) of the four compounds also exhibited potent anti‐trypanosomal activity with GI₅₀ values of 0.3–0.4 μM. All four active compounds represented derivatives modified at their C‐9 hydroxy group. With respect to anti‐proliferative activity and selectivity, 2e (epi‐N‐quinidyl‐N′‐bis(3,5‐trifluoromethyl)phenylthiourea) proved to be the most promising derivative for both cancer cells and bloodstream forms of T. b. brucei. The cytotoxic activity of compounds 1u , 1w , 2e and 3d was attributed to their ability to induce apoptosis in cancer cells. The results demonstrate the potential of cinchona alkaloid derivatives as novel anti‐cancer and anti‐trypanosome drug candidates.     

Anticancer activity of newly synthesized azaphenothiazines from NCI’s anticancer screening bank

The activity of the newly synthesized azaphenothiazines: tricyclic 10-substituted dipyridothiazines 1–9, pentacyclic 6-substituted diquinothiazines 10–22 and hexacyclic diquinothiazinium salt 23 was tested on 55–60 in vitro cell lines. The cell lines included nine types of cancer: leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer (National Cancer Institute, Bethesda, MD, USA). The features of the chemical substituent at the thiazine nitrogen atom confer the anticancer activity of diquinothiazines 10–23. Unexpectedly, the most active of the dipyridothiazines 1-9 was the unsubstituted compound 1 (the substituent is a hydrogen atom). The most cytotoxic compound was the half-mustard derivative 18. The GI₅₀ value of this compound was –7.06 (corresponding to 40 ng/ml) when tested on the melanoma cell line SK-MEL-5 and –6.0 – –6.62 using cell lines from various cancers including: leukemia (CCRF-CEM), the MOLT-4 cell line, colon cancer (HCT-116), central nervous system cancer (SNB-75 and SF-295), prostate cancer (PC-3), non-small cell lung cancer (NCI-H460 and HOP-92), ovarian cancer (IGROV1 and OVCAR-4) and breast cancer (MDA-MB-460). The ethylene group in the aminoalkylazaphenothiazines is as a good linker and is similar to the propylene and butylene linkers in aminoalkylphenothiazines. To our knowledge, this is the first demonstration of significant azaphenothiazine anticancer activity.     

Design,Synthesis, and Biological Evaluation of 1,5‐Diaryl‐1,2,4‐triazole Derivatives as Selective Cyclooxygenase‐2 Inhibitors

A series of 1,5‐diaryl‐1,2,4‐triazole derivatives were synthesized and evaluated as cyclooxygenase‐2 (COX‐2) inhibitors. The results of the preliminary biological assays in vivo showed that eight compounds 5b , 6b , 6c , 7c , 8b , 8d , 9c , and 9d have potent anti‐inflammatory activity (P < 0.01), while compounds 6b , 6c , and 9c exhibit marked potency. Compound 6c was then selected for further investigation. In the COX inhibition assay in vitro, compound 6c was identified as a potent and selective inhibitor of COX‐2 (COX‐2 IC₅₀ = 0.37 µM; SI = 0.018), being equipotent to celecoxib (COX‐2 IC₅₀ = 0.26 µM; SI = 0.015). In a rat carrageenan‐induced paw edema assay, 6c exhibited moderate anti‐inflammatory activity (35% inhibition of inflammation) at 2 h after administration of 15 mg/kg as an oral dose. A docking study also revealed that compound 6c binds in the active site of COX‐2 in a similar mode to that of the known selective COX‐2 inhibitor SC‐558.     

Preclinical pharmacokinetic and pharmacodynamic evaluation of thiazolidinone PG15: an anti‐inflammatory candidate

Objectives Novel 5‐benzilidene thiazolidinones have been synthesized and exhibited anti‐inflammatory activity. In this work one of the compounds of the thiazolidinone chemical series, (5Z,E)‐3‐[2‐(4‐chlorophenyl)‐2‐oxoethyl]‐5‐(1H‐indol‐3‐ ylmethylene)‐thiazolidine‐2,4‐dione (PG15) was investigated aiming to determine the drug's anti‐inflammatory potential in pre‐clinical studies. Methods Methods used included the in‐vitro inhibition of cyclooxygenase‐1 and ‐2, in‐vivo evaluation of anti‐inflammatory activity by air pouch and peritonitis models and the pharmacokinetic profile after intravenous (3 mg/kg) and oral (3 and 6 mg/kg) dosing to rats. Key findings A two‐compartment model with a fast distribution and an elimination half‐life of 5.9 ± 3.8 h described the PG15 plasma profile after intravenous dosing. PG15 showed an erratic and rapid absorption following oral administration with peak concentrations between 0.5 and 1 h. PG15 0.1 μM inhibited more than 30% and 13% of purified cyclooxygenase‐1 and ‐2 activity in vitro, respectively. A lack of dose dependency was observed for the anti‐inflammatory effect in the dose range investigated (0.8–50 mg/kg), with a maximum of 67.2 ± 4.6% inhibition of leucocyte migration in the carrageenan‐induced air pouch model obtained with the 3 mg/kg dose, similar to that observed for indometacin 10 mg/kg. Conclusions The erratic absorption of PG15 observed after oral dosing could explain the lack of anti‐inflammatory dose dependency.