Synthesis and Antitumour Activity of New Derivatives of Flavone-8-acetic Acid (FAA). Part 31): 2-Heteroaryl Derivatives

A range of 14 derivatives of flavone-8-acetic acid (FAA) with a heterocyclic substituent in place of the 2-phenyl group have been prepared and their anti-tumour activity evaluated in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A. Some of the compounds, notably 2c, d and s , showed significant in vivo activity and these require further studies in order to evaluate their potential for development.     

Synthesis and Antitumour Activity of New Derivatives of Flavone-8-acetic Acid (FAA). Part 2: Ring-Substituted Derivatives

A range of 18 derivatives of flavone-8-acetic acid (FAA) with substituents on the 2-phenyl group have been prepared and their anti-tumour activity evaluated in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A. There was no clear-cut relationship between in vitro and in vivo activity but the activity in each situation was found to be very sensitive to the precise substitution pattern with closely related isomers giving widely different activities. Some of the compounds, notably 10b,cj , and r , were active in vivo and these require further studies in order to evaluate their potential for development.     

Praziquantel Derivatives with Antischistosomal Activity: Aromatic Ring Modification

A series of aromatic ring‐modified praziquantel derivatives were prepared and evaluated against juvenile and adult stage of Schistosoma japonicumin. Several analogs comparable in activity to the drug praziquantel have been identified based on in vitro and in vivo japonuicum schistosomes worm viability assay. Structure and activity relationship of these praziquantel aromatic ring‐modified compounds was revealed. Specifically, a compound in which a bromine has been introduced in the aromatic ring of praziquantel demonstrated close antischistosomal activity to praziquantel in vivo.     

Activity of flavone acetic acid (NSC-347512) against solid tumors of mice

Flavone acetic acid (FAA) is a new antitumor agent that has recently entered Phase I clinical trials. In preclinical studies, we have found that FAA was broadly active against a variety of transplantable solid tumors of mice (colon #51, #07, #10, #26; pancreatic ductal adenocarcinomas #02 and #03; mammary adenocarcinoma #16/C/Adr; M5076 reticulum cell sarcoma and Glasgow's osteosarcoma). FAA was curative for colon adenocarcinoma # 10 and pancreatic ductal adenocarcinoma # 03. Thus, for the first time an agent has been identified with very broad, perhaps nearly universal solid tumor activity. FAA was also found to be orally active and stable in solution at 37 °C for 48 h. FAA was selectively cytotoxic in vitro for solid tumors over leukemias L1210 and P388 (in a soft-agar colony formation assay), thus correlating cellular selectivity in vitro with in vivo antitumor activity. The finding that FAA was active in vitro, established that the agent did not need metabolism (activation) outside the tumor cell. The main drawback of FAA was an unusual threshold behavior in which only a narrow range of doses were active and splitting the dose markedly decreased activity.     

Antiproliferative Activity and Phototoxicity of some Methyl Derivatives of 5–Methoxypsoralen and 5–Methoxyangelicin

Abstract: The in vitro antiproliferative activity and in vivo phototoxicity of some methyl derivatives of 5–methoxypsoralen and 5–methoxyangelicin, i.e. 4,4′–dimethyl–5–methoxyangelicin (compound I), 3,4′–dimethyl–5–methoxyangelicin (compound II), 4,4′–dimethyl–5–methoxypsoralen (compound III); and 3.4′–dimethyl–5–methoxypsoralen (compound IV), have been investigated. The effects of the compounds were evaluated in vitro on HL60 and A431 cells, using 5–methoxypsoralen as the reference compound. In both cell lines compound I, II and III showed better antiproliferative activity than compound IV and 5–methoxypsoralen. Scanning electron microscopy revealed that all the compounds induced the formation of blebs and blisters on a A431 cell surface. Significant variations in the nuclear area strictly related to the toxicity of the compounds have been shown in both cell lines. Skin irritancy in vivo was evaluated by mean of histopathological responses on guinea–pig skin. For each compound a damage index was determined by morphometrical analysis of empty spaces in the epidermis. Histopathology revealed skin phototoxicity of compounds which lacked erythemogenic activity by visual scoring. By coupling cytotoxicity data in vitro to skin sensitization ones in vivo, compound I proved a promising candidate for use in clinical trials since due to a high inhibitory effect on the growth of human cell lines coupled to low skin phototoxicity.     

Antituberculosis activity of some nitrofuran derivatives

A series of 4,6-disubstituted 2-(5-nitrofurfurylidenehydrazino)-1,3,5-triazines has been synthesized. Some of these compounds possessed good antibacterial activity against Mycobacterium tuberculosis in vitro and moderate activity in vivo (the activity in vivo was observed only with high dosages compared with compounds in clinical use and the results were also irregular). The most active compounds are triazinylhydrazones of 5-nitro-2-furaldehyde in which the triazine ring is substituted with two amino-groups, at least one of which is an (α-branched chain alkyl)- or cycloalkylamine. Structure- anti-tuberculosis activity relations for these compounds are discussed.     

Hydroxycamptothecin liposomes based on thermal and magnetic dual-responsive system: preparation,in vitro and in vivo antitumor activity,microdialysis-based tumor pharmacokinetics

Due to the absence of lactone form of hydroxycamptothecin, the commercially available hydroxycamptothecin injection exhibits inefficient therapeutic effects. In this study, we constructed a novel delivery system (thermosensitive magnetic liposomes) that protects lactone form of hydroxycamptothecin from blood or water. After hydroxycamptothecin was loaded into the thermosensitive magnetic liposome (HCPT/TML), its in vitro and in vivo antitumor activity and microdialysis-based tumour pharmacokinetics were determined. The results demonstrated that HCPT/TMLs possessed favourable physicochemical features and significant cytotoxicity against the Huh-7 cells in vitro. In the in vivo antitumor study and tumour pharmacokinetics, HCPT/TMLs displayed effective targeting delivery and antitumor effects, which corresponded to the determined hydroxycamptothecin concentration in tumour tissue. In conclusion, this thermal and magnetic dual-responsive system can efficiently deliver hydroxycamptothecin to tumour tissue and has great potential application in cancer treatment.     

Synthesis and antitumor activity of a series of lactone-opened camptothecin derivatives

A series of E-ring lactone-opened camptothecin (CPT) derivatives bearing with terminal aza-heterocyclic groups were synthesized, and their antitumor activity was evaluated both in vitro and in vivo. Hydroxyl-amide analogues with morpholin-4-yl displayed excellent antitumor activity in vitro and efficient inhibition on tumor xenograph model in nude mice. Ester-amide compounds acted less active in vitro cytotoxicity and lower inhibition activity in vivo. Substitutions at 7- and 10- positions favored the antitumor activity.     

Patent Evaluation: Sampangine and Derivatives Useful as Antifungal Agents

Summary

Novelty: A novel compound, 3-methoxy-sampangine, and its analogues, which may be useful as antifungal agents, are disclosed. Compositions containing these compounds are also described. Sampangines are stated to be particularly effective against Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus.

Biology: Antifungal activity was determined by in vitro evaluation using a modified agar-well diffusion assay technique. These compounds exhibited in vitro activity against one or more fungal pathogens at potencies comparable to, and in many cases better than, amphotericin B.

Chemistry: The syntheses of these compounds are described in detail. Seven examples are given. Four compounds are specifically claimed, including 3-methoxy-sampangine.

Structure:     

Potential Biologically Active Agents,XXXII. Synthesis and Antiviral Activity of Some 3-(Arylthiosemicarbazono)-2-indolinones

A series of 3-(arylthiosemicarbazono)-2-indolinones 1 , 1-methyl-3-(arylthiosemicarbazono)-2-indolinones 2 and 1-(aminomethyl)-3-(arylthiosemicarbazono)-2-indolinones 3 have been synthesised. All compounds were screened for their antiviral activity against Sunnhemp rosette virus (SRV) in vitro as well as in vivo. Twelve compounds show significant antiviral activity.     

虎杖苷及其衍生物抑制SGLT2降血糖活性研究

目的 揭示虎杖苷及其衍生物抑制钠-葡萄糖协同转运体2（sodium-glucose cotransporter 2,SGLT2）活性的构效关系。方法 以虎杖苷为起始物,经S_N2取代反应、催化氢化获得5个衍生物,以¹H-NMR和HR-ESI-MS进行结构表征。采用荧光标记的1-脱氧葡萄糖{1-[N-（7-nitrobenz-2-oxa-1,3-diazol-4-yl）amino]-1-deoxy-D-glucose,1-NBDG}作为底物对虎杖苷及其衍生物进行体外抑制SGLT2活性测试,对衍生物1b进行体内活性测试,大鼠口服糖耐量实验及促尿糖实验。结果 获得5个虎杖苷衍生物,¹H-NMR和HR-ESI-MS表征结构正确,体外实验显示虎杖苷及其衍生物能较好地抑制SGLT2活性,且化合物1b在10^-5 mol·L^-1时对SGLT2的抑制率达98.6%,但是大鼠体内实验显示1b在120 mg·kg^-1时抑糖率只有11%,尿糖量只有122 mg每200 g,其活性远远低于阳性对照药达格列净。结论 虎杖苷及其衍生物作为O-芳基糖苷化合物具有较弱的抑制SGLT2降血糖活性,其分子结构对后续设计新的C-芳基糖苷SGLT2抑制剂具有一定的指导意义。     

Design,Synthesis and Biological Evaluation of Pazopanib Derivatives as Antitumor Agents

A novel series of pazopanib derivatives were designed, synthesized, and evaluated for their inhibitory activity against a series of kinases including VEGFR‐2, EGFR, AKT1, ALK1, and ABL1. The anti‐angiogenic activities ex vivo of some compounds were also investigated. Compounds P2d and P2e demonstrated outstanding inhibitory activity against VEGFR‐2 and ABL1 and higher anti‐angiogenic activity compared with Pazopanib, the reference standard. These two compounds ( P2d and P2e ) could be used as novel lead compounds for further development of anticancer agents.     

Evaluation of in vitro antioxidant,anticancer and in vivo antitumour activity of Termitomyces clypeatus MTCC 5091

Context: Termitomyces clypeatus (Lyophyllaceae) is a filamentous edible mushroom, having ethnomedicinal uses. However, information about the antioxidant, anticancer and antitumour properties of this mushroom remains to be elucidated.

Objective: The study examines the in vitro antioxidant, anticancer and in vivo antitumour activity of T. clypeatus.

Materials and methods: Antioxidant activity was evaluated with seven in vitro assays. Cytotoxicity of T. clypeatus was tested against a panel of cancer cells lines including U373MG, MDA-MB-468, HepG2, HL-60, A549, U937, OAW-42 and Y-79 using MTT assay. The antitumour activity of aqueous extract was evaluated against Ehrlich ascites carcinoma (EAC) tumour model in Swiss albino mice.

Results: HPLC analysis of aqueous extract revealed the presence of sugar entities. Termitomyces clypeatus showed excellent in vitro antioxidant activity. Termitomyces clypeatus was found cytotoxic against all cancer cells, among which it showed higher activity against U937 (IC₅₀ 25?±?1.02?μg/mL). Treatment of EAC-bearing mice with varied doses of aqueous extract significantly (p?<?0.01) reduced tumour volume, viable tumour cell count and improved haemoglobin content, RBC count, mean survival time, tumour inhibition and % increase life span. The enhanced antioxidant status in treated animals was evident from the decline in the levels of lipid peroxidation, increased levels of glutathione, catalase and superoxide dismutase.

Discussion: The analyzed data indicate that the aqueous extract of T. clypeatus exhibits significant antitumour activity, which might be due to the antioxidant effects on EAC bearing hosts.

Conclusion: Termitomyces clypeatus possesses anticancer activity, valuable for application in food and drug products.     

Studies of the mode of action of antitumour triazenes and triazines—V. The correlation of the in vitro cytotoxicity and in vivo antitumour activity of hexamethylmelamine analogues with their metabolism

Experiments were conducted to ascertain whether the antitumour activity of hexamethylmelamine analogues correlated with their in vitro cytotoxicity and metabolism. Two analogues, namely pentamethylmelamine (PMM) and 2,2,4,4-tetramethylmelamine (TMM), and hexamethylmelamine (HMM) itself were shown to be active towards the murine ADJ/PC6A (PC6) plasmacytoma; another three, 2-chloro-4,6-bis(dimethylamino)-1,3,5-triazine (CBDT), 2,4-bis-(dimethylamino)-6-hydrazino-1, 3,5-triazine (HBDT) and 2,4,6-trimethylmelamine (TriMM) were inactive against the same tumour. The cytotoxicity of these compounds was examined against a PC6 tumour cell line in vitro. In the absence of liver microsomal activation only CBDT proved to be significantly cytotoxic at a concentration of 5 mM. In the presence of murine liver microsomes the three active antitumour agents were all cytotoxic at this concentration whereas HBDT and TriMM remained non-toxic. The degree of cytotoxicity correlated with the extent of metabolism for these analogues. The products of biotransformation of these compounds were stable precursors of formaldehyde (presumably N-hydroxymethyl intermediates) (FP) rather than formaldehyde itself. After injection of these 6 compounds to Balb/c mice the levels of FP generated in the plasma were markedly greater for the three active antitumour agents than for the inactive analogs. No free formaldehyde was detected in the plasma after administration of any of the compounds.These results suggest that for these compounds in vitro cytotoxicity correlates with in vitro biotransformation and their antitumour activity correlates with plasma levels of FP generated by metabolism in vivo.     

Synthesis,molecular docking,and pharmacological evaluation of N‐(2‐(3,5‐dimethoxyphenyl)benzoxazole‐5‐yl)benzamide derivatives as selective COX‐2 inhibitors and anti‐inflammatory agents

A series of N‐(2‐(3,5‐dimethoxyphenyl)benzoxazole‐5‐yl)benzamide derivatives ( 3am ) was synthesized and evaluated for their in vitro inhibitory activity against COX‐1 and COX‐2. The compounds with considerable in vitro activity (IC₅₀ < 1 μM) were evaluated in vivo for their anti‐inflammatory potential by the carrageenan‐induced rat paw edema method. Out of 13 newly synthesized compounds, 3a , 3b , 3d , 3g , 3j , and 3k were found to be the most potent COX‐2 inhibitors in the in vitro enzymatic assay, with IC₅₀ values in the range of 0.06–0.71 μM. The in vivo anti‐inflammatory activity of these six compounds ( 3a , 3b , 3d , 3g , 3j , and 3k ) was assessed by the carrageenan‐induced rat paw edema method. Compounds 3d (84.09%), 3g (79.54%), and 3a (70.45%) demonstrated significant anti‐inflammatory activity compared to the standard drug ibuprofen (65.90%) and were also found to be safer than ibuprofen, by ulcerogenic studies. A docking study was done using the crystal structure of human COX‐2, to understand the binding mechanism of these inhibitors to the active site of COX‐2.

     

Patent Evaluation: Hydrogenated Rapamycin Derivatives as Antifungal Agents

Summary

Novelty: Hydrogenated derivatives of rapamycin are disclosed as antifungal agents.

Biology: Data are presented which show that both claimed compounds are less active against five strains of Candida albicans than the parent rapamycin. 1,2-Dihydrorapamycin is significantly less active, whereas the 1,2,3,4-tetrahydro derivative was generally only half as effective (MIC = 0.006 μg/ml, compared with 0.003 μg/ml). However, Candida albicans 3669 was more sensitive to the tetrahydroderivative (MIC = 0.0125 μg/ml) than rapamycin (MIC = 0.025 μg/ml). Both new derivatives were relatively inactive in in vitro LAF and in vivo PLN tests and hence lack the immunosuppresive activity associated with rapamycin.

Chemistry: 1,2-Dihydro and 1,2,3,4-tetrahydro rapamycin were prepared by high pressure hydrogenation of rapamycin, which employs tris(triphenylphosphine)rhodium(I)chloride as a catalyst.     

New Benzofuran Derivatives as an Antioxidant Agent

A series of substituted benzofuran derivatives were synthesized and characterized by spectral data. Some of the synthesized compounds were tested for in vitro antioxidant activity. Some of them have shown very good antioxidant activity. These compounds were also tested for antimicrobial activity against microbial strains viz. staphylococcus aureus (NCIM 5021) and salmonella typhimurium (NCIM 2501), but none of them showed any activity against these microorganisms.     

Xanthone Derivatives as Potential Anti-cancer Drugs

Xanthone derivatives have been shown to be potent inhibitors of tumour growth. Oxygenated xanthones and [3-(dialkylamino)-2-hydroxypropoxy]xanthones have been prepared and tested for in-vitro inhibition of human PLC/PRF/5, KB and 212 cells. Structure-activity analysis indicated epoxidation of the hydroxyxanthone increased cytotoxicity against tumour cells but ring-opening of the epoxide group with dialkylamine did not enhance the anti-tumour activity. Further evaluation of three of the most active compounds 2, 6-, 3, 6-, and 3, 5-di(2,3-epoxypropoxy)xanthone (compounds 10a, 11a , and 12a , respectively) in DNA, RNA and protein synthesis of tumour cells showed potent inhibitory activity. The 3,5-di(2,3-epoxypropoxy)xanthone also showed potent inhibitory activity against 212 cells, a Ha-ras oncogene-transformed NIH 3T3 cell line. The results indicated that compounds 10a and 12a are potent anti-tumour agents which not only suppressed cellular DNA, RNA and protein synthesis but also specifically inhibited the Ha-ras oncogene in 212 cells.     

Synthesis and Antimycobacterial Activity of a Novel Series of Isonicotinylhydrazide Derivatives

A novel series of 14 new isonicotinyl hydrazide derivatives 2a – g , 3a – g containing a 4‐thiazolidinone / 2‐azetidinone nucleus were synthesized by reacting N′‐substituted arylidene / heteroarylidene isonicotinyl hydrazide 1a – g with thioglycollic acid in the presence of dry benzene and with chloroacetyl chloride in the presence of triethylamine, respectively. Structures of all newly synthesized compounds were characterized on the basis of elemental analyses and spectral data (IR and ¹H‐NMR). All the title compounds were tested for their in‐vitro antimycobacterial activity against Mycobacterium tuberculosis H₃₇Rv using Alamar‐Blue susceptibility test, and the activity is expressed as the minimum inhibitory concentration (MIC) in μg/mL. Among the series, compounds 2b , 2g , 3b , and 3g displayed an encouraging antimycobacterial activity profile as compared to that of the reference drugs isoniazid / rifampicin.     

Synthesis and Anticholinergic Activity of 4‐hydroxycoumarin Derivatives Containing Substituted Benzyl‐1,2,3‐triazole Moiety

A series of 4‐hydroxycoumarin‐derived compounds 8a‐p containing N‐benzyl‐1,2,3‐triazole motif were designed as AChE inhibitors. The title compounds were obtained conveniently using multicomponent click reaction. The in vitro anticholinesterase evaluation of synthesized compounds against AChE and BuChE showed that some of them are potent and selective inhibitors of AChE. Among them, 2‐chlorobenzyl derivative 8k showed the most potent activity against AChE (IC₅₀ = 0.18 μm ). Its activity was also superior to that of standard drug tacrine. The kinetic study and molecular docking simulation of the most potent compound 8k were also described.