Synthesis of chalcone derivatives on steroidal framework and their anticancer activities

Chalcone derivatives on estradiol framework have been synthesized. Some of the derivatives showed potent anticancer activity against some human cancer cell lines. Compounds 9 and 19 showed potent activity against MCF-7, a hormone dependent breast cancer cell line. Chalcone 7 was further modified to the corresponding indanone derivative (19) using the Nazarov reaction, which showed better activity than the parent compound against the MCF-7 breast cancer cell line. Active anticancer derivatives were also evaluated for osmotic hemolysis using the erythrocyte as a model system. It was observed that chalcone derivatives showing cytotoxicity against cancer cell lines did not affect the fragility of erythrocytes and hence may be considered as non-toxic to normal cells.     

Synthesis of chalcone analogues with increased antileishmanial activity

Eighteen analogues of an active natural chalcone were synthesized using xanthoxyline and some derivatives, and these analogues were tested for selective activity against both promastigotes and intracellular amastigotes of Leishmania amazonensis in vitro. Three analogues (10, 12, and 19) containing nitro, fluorine or bromine groups, respectively, displayed increased selective activity against the parasites as compared with the natural chalcone. The nitrosylated chalcone 10 was also tested intralesionally in infected mice and was found to be as effective as Pentostan reference drug at a dose 100 times higher than that of the chalcone in controlling both the lesion growth and the parasite burden.     

Norcantharimides, synthesis and anticancer activity: Synthesis of new norcantharidin analogues and their anticancer evaluation

A range of amines was reacted with norcantharidin (2) to provide the corresponding norcantharimides (9-43). Treatment of norcantharidin with allylamine afforded the corresponding allyl-norcantharimide (20) which was amenable to epoxidation (mCPBA, 22) and subsequent ring opening (MeOH/H(+); 23) or alternatively, osmylation (OsO(4)/NMO; 24). These simple synthetic modifications of 2 facilitated the development of a novel series of norcantharimides displaying modest to good broad spectrum cytotoxicity against HT29 and SW480 (colorectal carcinoma); MCF-7 (breast adenocarcinoma); A2780 (ovarian carcinoma); H460 (lung carcinoma); A431 (epidermoid carcinoma); DU145 (prostate carcinoma); BE2-C (neuroblastoma); and SJ-G2 (glioblastoma). Analogues possessing a C(10), C(12) or C(14) alkyl chain or a C(12) linked bis-norcantharimide displayed the highest levels of cytotoxicity.     

Synthesis of some imidazolyl-thioacetyl-pyrazolinone derivatives and their antinociceptive and anticancer activities

In this study, some 4-(1,5-diarylimidazol-2-yl)thioacetyl-1-phenyl-2,3-dimethyl-3-pyrazoline-5-one derivatives were prepared by reacting 4-(2-chloroacetyl)-1-phenyl-2,3-dimethyl-3-pyrazoline-5-one and 2-mercapto-1, 5-diarylimidazole derivatives. The antinociceptive and anticancer activities of the compounds obtained were investigated. It was observed that some of the compounds, 2a, 2d, 2g, and 2j, showed remarkable antinociceptive activity, and one of the compounds, 2i, showed weak anticancer activity.     

Synthesis and anticancer activity studies of indolylisoxazoline analogues

A new library of thirteen indolylisoxazolines 6a–m has been synthesized by the treatment of indolylchalcones with hydroxylamine hydrochloride. Evaluation of anticancer activity of indolylisoxazolines 6a–m led to the identification of potent compounds 6c–d, 6i and 6l, with IC₅₀ ranging 2.5–5.0?µM against the tested cancer cell lines. Using a number of complementary techniques such as acridine orange/ethidium bromide staining, PARP1 cleavage and DNA strand breaks assay, we show that the compounds 6c and 6i induce apoptosis in highly aggressive C4-2 cells. Our data further revealed that 6c and 6i inhibited C4-2 cells proliferation without inducing reactive oxygen species (ROS). Finally, we show that compounds 6c and 6i also potently inhibit cell migration, indicating these compounds have the potential to serve as effective anti-cancer agents.     

Synthesis and in vitro leishmanicidal activity of some hydrazides and their analogues

Twenty-one hydrazides were synthesized by treating different esters with hydrazine hydrate. Substituted hydrazides were obtained by treating hydrazides with alkyl/aryl/acyl halides. Some of these compounds exhibit potential in vitro leishmanicidal activity. The structures of all the synthesized compounds were confirmed by spectroscopic analysis.     

Synthesis, characterization, electrochemical studies and antitumor activity of some new chalcone analogues containing ferrocenyl pyrazole moiety

A series of new α,β-unsaturated conjugated ketones containing ferrocenyl pyrazole unit were synthesized and fully characterized by IR and NMR spectroscopy. Electrochemical characterization of subject compounds was performed by means of cyclic voltametry. The in vitro cytotoxic activity of all the synthesized compounds was studied against cervix adenocarcinoma HeLa, melanoma Fem-x and myelogenous leukemia K562 cell lines by the MTT method. Derivative 1l containing 3-pyridyl moiety exhibited a better cytotoxic activity in the cell growth inhibition of K562 cell lines in comparison with cisplatin as a reference compound.     

Structure-antiemetic-activity of some diarylheptanoids and their analogues

The structure-activity relationship of diarylheptanoids and their analogues inhibitory of emesis induced by copper sulfate in young chicks was investigated by testing 19 compounds. The compounds are 5 diarylheptanoids isolated from Alpinia katsumadai (Zingiberacea), 5 chemical derivatives of them, 6 analogues isolated from Zingiber officinale rhizome (Zingiberaceae), and 3 analogues available on the market. Among them, two types of essential functional structure of diarylheptanoids and their analogues showed the inhibitory effects against emesis.     

Structural analogues of diosgenyl saponins: Synthesis and anticancer activity

Saponins display various biological activities including anti-tumor activity. Recently intensive research has been focused on developing saponins for tumor therapies. The diosgenyl saponin dioscin is one of the most common steroidal saponins and exhibits potent anticancer activity in several human cancer cells through apoptosis-inducing pathways. In this paper, we describe the synthesis of several diosgenyl saponin analogues containing either a 2-amino-2-deoxy-β-d-glucopyranosyl residue or an α-l-rhamnopyranosyl-(1→4)-2-amino-2-deoxy-β-d-glucopyranosyl residue with different acyl substituents on the amino group. The cytotoxic activity of these compounds was evaluated in MCF-7 breast cancer cells and HeLa cervical cancer cells. Structure–activity relationship studies show that the disaccharide saponin analogues are in general less active than their corresponding monosaccharide analogues. The incorporation of an aromatic nitro functionality into these saponin analogues does not exhibit significant effect on their cytotoxic activity.     

Synthesis and radioiodination of some daunorubicin and doxorubicin derivatives

Daunorubicin and doxorubicin are efficient agents for cancer treatment. Their clinical efficacy is, however, hampered by their indiscriminant toxicity. This problem may be circumvented by encapsulating the drugs in liposomes and selectively targeting the tumor cells using tumor targeting agents. Furthermore, the antitumor effect could be enhanced by attaching the Auger electron emitter, (125)I, to daunorubicin and doxorubicin derivatives. In this context a number of ester, amide, and amine derivatives of daunorubicin and doxorubicin were synthesized. Benzoic acid ester derivatives of daunorubicin were synthesized by nucleophilic esterification of the 14-bromodaunorubicin with the potassium salt of the corresponding benzoic acid, resulting in good yields. Nicotinic acids and benzoic acids, activated with a succinimidyl group, were coupled to the amino group of daunorubicin to give the corresponding amide derivatives. Amine derivatives were obtained by the reductive amination of aromatic aldehydes with daunorubicin hydrochloride. The stannylated ester and amide derivatives were used as precursors for radioiodination. Radiolabeling with (125)I was performed using chloramine-T as an oxidant. The optimized labeling resulted in high radiolabeling yields (85-95%) of the radioiodinated daunorubicin and doxorubicin derivatives. Radioiodination of the amines was conducted at the ortho position of the activated phenyl rings providing moderate radiochemical yields (55-75%).     

Synthesis of cryptolepine analogues as potential bioreducible anticancer agents

A series of 10 novel nitro-analogues of cryptolepine (1) has been synthesised and these compounds were evaluated for their in-vitro cytotoxic properties as well as their potential for reductive activation by the cytosolic reductase enzymes NQO1 and NQO2. Molecular modelling studies suggest that cryptolepine is able to fit into the active site of NQO2 and thus raising the possibility that nitro-analogues of 1 could act as bioreductive prodrugs and be selectively reduced by NQO1 and NQO2 to more toxic species in cancer cells in which these enzymes are over-expressed. Analogues were screened against the RT112 cell line (high in NQO2), in the presence and absence of the essential cofactor dihydronicotinamide riboside (NRH), whereby all analogues were shown to be cytotoxic (IC50<2microM) in the absence of NRH. With the addition of NRH, one analogue, 2-fluoro-7,9-dinitrocryptolepine (7), exhibited a 2.4-fold increase in cytotoxic activity. Several nitro-derivatives were also evaluated as substrates for purified human NQO1 and analogues that were found to be substrates were subsequently tested against the H460 (high NQO1) and BE (low NQO1) cell lines to detect in-vitro activation by NQO1. The analogue 8-chloro-9-nitrocryptolepine (9) was found to be the best substrate for NQO1 but it was not more toxic to H460 than to BE cells. Fluorescence laser confocal microscopy of 1 and several analogues showed that in contrast to 1 the analogues were not localised into the nucleus suggesting that their cytotoxic mode(s) of action are different. This study has identified novel substrates for both NQO1 and NQO2 and further work on nitrocryptolepine derivatives as a lead towards novel anticancer agents would be worthwhile.     

Assessment of the effect of cyclic chalcone analogues on mitochondrial membrane and DNA

The cytotoxic and protective effects of selected synthetic chalcone analogues have been shown in previous studies. We studied their cytotoxic effect on the modification of mitochondrial membrane potential and on DNA. The first spectral information about the methoxy group as well as the dimethylamino substituent in E-2-arylmethylene-1-benzosuberones molecule was obtained by absorption and emission spectra. The cytotoxic effect of both cyclic chalcone analogues on DNA were detected by alkaline single-cell gel electrophoresis. Better fluorescent chalcone analogue E-2-(4′-dimethylamino-benzylidene)-1-benzosuberone was studied further in fresh isolated mitochondria. The decrease of rat liver mitochondria membrane potential (Δψ) was observed by fluorescence emission spectra. For the collapsing of mitochondrial potentials and as the negative control of mitochondrial function the CCCP uncoupler was used. The absorption maximum of the methoxy group was found at a shorter wavelength (λ = 335 nm) than that of the dimethylamino group (λ = 406 nm). The excitation spectra were very similar to the absorption spectra for both molecules but the emission spectra showed a better fluorescence for dimethylamino derivative. After the addition of E-2-(4′-dimethylamino-benzylidene)-1-benzosuberone to the intact mitochondria the decrease of mitochondrial membrane potential Δψ was observed by emisssion fluorescence spectra. Both cyclic chalcone analogues induced DNA damage, which was detected by alkaline comet assay. Mainly the apoptotic cells were detected, but necrotic cells were also present. Similarities in the percentages of DNA migration from the head were observed in both treatment groups. Both benzosuberones, with dimethylamino- and methoxy- substituent, were very active biologically, as shown by DNA results of the comet assay. Due to its better fluorescence properties, only the fluorophore with dimethylamino substituent was selected for further study of the function of rat liver mitochondria. Decline of mitochondrial function as well as mitochondrial DNA damage were evident between experimental and control groups.     

Synthesis and biological evaluation of novel triptolide analogues for anticancer activity

Three types of novel triptolide analogues with 9,11-olefin (3–5), five-membered unsaturated lactam ring (6–7) or A/B cis ring junction (8–14) were synthesized. Although with 9,11-olefin instead of 9,11-β-epoxide, compound 4a was much more active than the parent natural triptolide (1) with the lowest IC₅₀ value of 0.05 nM for SKOV-3 cells, clearly challenging the traditional viewpoint on the necessity of 9,11-β-epoxide group of triptolide. In addition, structure–activity relationships for three classes of compounds were studied.     

Synthesis and structure-activity studies of antofine analogues as potential anticancer agents

Due to the profound cytotoxicities and interesting biochemical aspects, phenanthroindolizidine alkaloids have received an attention as potential therapeutic leads. To define the features of the molecule that are essential for cytotoxicity, we have synthesized and evaluated a series of phenanthroindolizidine alkaloid, antofine, analogues with different substituents on the phenanthrene ring. The systematic structure activity relationship studies elucidate the essential functional group requirement of phenanthrene ring, providing the basis for further development of phenanthroindolizidine alkaloids.     

Synthesis of new 7-chloroquinolinyl thioureas and their biological investigation as potential antimalarial and anticancer agents

New 7-chloroquinolinyl thiourea derivatives derived from the corresponding 4,7-dichloroquinoline isothiocyanate were synthesized and evaluated for in vitro antimalarial and anticancer activity. The most active compound from the series displayed an inhibitory IC(50) value of 1.2 microM against the D10 strain of Plasmodium falciparum. Lack of cytotoxicity towards HeLa cells indicates selectivity towards parasites.     

Synthesis and binding studies of some epibatidine analogues

A series of epibatidine analogues and their positional isomers bearing an 8-azabicyclo[3.2.1]octane moiety is described. Some of the compounds, especially those containing 8-azabicyclo[3.2.1]oct-2-ene moiety show high affinity for the nicotinic cholinergic receptor.     

Synthesis and anti-virus activity of some nucleosides analogues

New 3'-, 5'-, 5-bromo-2'-deoxyuridine (3a-g) and 3'-, 5'-thymidine (4a-i) analogues with amino acid and peptide residues were synthesized and evaluated for antiviral activity. The influence of long peptide chains, essential amino acids and the effect of this structural modification on the antiviral activity has been also reported. Three 5-bromo-2'-deoxyuridine derivatives containing glycyl-, glycyl-glycyl- and glycyl-glycyl-glycyl- residues (3a, 3b, 3c) showed a strong activity against the herpes virus PsRV and a moderate one vs. HSV-1. The corresponding thymidine analogues were considerably less effective, and only compounds 4d and 4h showed a borderline effect against PsRV.     

Synthesis and anticancer evaluation of vitamin K(3) analogues

Novel vitamin K(3) analogues were synthesized and evaluated for their anticancer activity. Compound 6, 9, 10, 11, 14, and (+/-)15 demonstrated a strong inhibitory activity against the tumor cells of A-549, Hep G2, MCF7, MES-SA, MES-SA/Dx5, MKN45, SW-480, and TW-039. Compound (+/-)15 displayed potent tumor cell cytotoxicity, and compound 14 selectively affected MCF7, even though it did not influence normal cells Detroit551 and WI-38. Compound (+/-)15 inhibited MES-SA and MES-SA/Dx5, and this specific result shows that compound (+/-)15 may become a good anticancer drug candidate.     

Synthesis, screening and quantitative structure-activity relationship (QSAR) studies of some glutamine analogues for possible anticancer activity

We described the syntheses, biological activities and QSAR studies of 36 new 5-n-substituted-2-(substituted benzenesulphonyl) glutamines 6-41 with different substitutions. These compounds were designed as structural analogues of most reactive amino acid, 'glutamine' (GLN), especially in the tumor cells. They present the new basic lateral chains at R(5) position as well as different substitutions at 2', 3', 4', and 5' positions on the benzene ring. The synthesized compounds have been tested for antitumor activity against Ehrlich ascites carcinoma (EAC) in Swiss albino mice using percentage inhibition of tumor weight as inhibitory parameter. In order to elucidate the structural requirements for antitumor activity, quantitative structure-activity relationship (QSAR) studies have been performed using extra thermodynamic model of Hansch. QSAR equations showed that the electronic parameter (sigma) on the aromatic ring system, steric parameter (Es) and to some extent Sterimol length of the substituent (L) on the aliphatic side chain correlate significantly with the antitumor activity. Resonance factor occupies the major electronic contribution on the aromatic ring system to the activity.     

Synthesis and anticancer effect of chrysin derivatives

A series of chrysin derivatives, prepared by alkylation, halogenation, nitration, methylation, acetylation and trifluoromethylation, were tested in vitro against human gastric adenocarcinoma cell line (SGC-7901) and colorectal adenocarcinoma (HT-29) cells. Among these derivatives of chrysin, 5,7-dimethoxy-8-iodochrysin 3 and 8-bromo-5-hydroxy-7-methoxychrysin 11 have the strongest activities against SGC-7901 and HT-29 cells, respectively. 5,7-Dihydroxy-8-nitrochrysin 12 were found to have strong activities against both SGC-7901 and HT-29 cells.