Synthesis of novel chalcones through palladium-catalyzed CO cross-coupling reaction of bromo-chalcones with ethyl acetohydroxamate and their antiplasmodial evaluation against Plasmodium falcipuram in vitro

An efficient method for palladium-catalyzed CO cross-coupling of ethyl acetohydroxamate (EAcHO) with 4-bromo-chalcones has been developed to synthesize novel chalcones. The two supporting ligands, namely tBuXPhos (L7), and cataCXium®PIntB (L16) were found to be effective ligands towards the Pd-catalyzed CO cross-coupling reaction to afford the desired product in moderate to excellent yields (50–99%). The coupled products were screened for in vitro blood stage antiplasmodial activity against Plasmodium falciparum (3D7) using the [³H] hypoxanthine incorporation inhibition assay. Of the twenty two compounds screened, eleven showed good antiplasmodial activity with IC₅₀ values ranging from 6–16 μg/mL. The selected active molecules 11, 16, 22, (IC₅₀ 12 μg/mL) and 19 (IC₅₀ 6 μg/mL) were studied for their cytotoxic effect against HepG2 Cells (human hepatocellular liver carcinoma cell lines), showing the selectivity index (SI) values are greater than 4 except chalcone 22. Our result demonstrates a methodology for synthesizing novel chalcones as a new class of antiplasmodial agent.     

Synthesis of thiazolidine-2,4-dione derivatives: anticancer,antimicrobial and DNA cleavage studies

In the search of efficient anticancer agents, here, new 5-(4-alkylbenzyledene)thiazolidine-2,4-dione derivatives (5a–g) have been successfully synthesized and characterized and are evaluated for anticancer and antimicrobial activities using DNA cleavage studies. In vitro studies on anticancer activity of compound 5d (NSC: 768619/1) was done against the full panel of 60 human tumor cell lines. The five-level dose activity results revealed that, the compound 5d was active against all the cell lines, it has shown potential activity against leukemia SR (GI₅₀: 2.04 μM), non-small cell lung cancer NCI-H522 (GI₅₀: 1.36 μM), colon cancer COLO 205 (GI₅₀: 1.64 μM), CNS cancer SF-539 (GI₅₀: 1.87 μM), melanoma SK-MEL-2 (GI₅₀: 1.64 μM), ovarian cancer OVCAR-3 (GI₅₀: 1.87 μM), renal cancer RXF 393 (GI₅₀: 1.15 μM), prostate cancer PC-3 (GI₅₀: 1.90 μM), and breast cancer MDA-MB-468(GI₅₀: 1.11 μM). DNA cleavage studies revealed that at 50 μg/mL concentration, partial DNA digestion was observed and when the concentration is increasing to threefold (150 μg/mL), complete linear DNA digestion and partial supercoiled DNA digestion was observed. Further antimicrobial studies indicate that all the synthesized compounds except compound 5a possess prominent activity against all the screened microbial species. This study throws a ray of light in the field of anticancer drugs.     

Carbonic anhydrase inhibitors. Biphenylsulfonamides with inhibitory action towards the transmembrane,tumor-associated isozymes IX possess cytotoxic activity against human colon,lung and breast cancer cell lines

Reaction of 4,4-biphenyl-disulfonyl chloride with aromatic/heterocyclic sulfonamides also incorporating a free amino group, such as 4-aminobenzenesulfonamide, 4-aminoethyl-benzenesulfonamide, 6-chloro-4-aminobenzene-1,3-disulfonamide or 5-amino-1,3,4-thiadiazole-2-sulfonamide afforded bis-sulfonamides which have been tested as inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4..2.1.1). The compounds were rather modest inhibitors of isozymes CA I and XII, but were more efficient as inhibitors of the cytosolic CA II and transmembrane, tumor-associated CA IX (inhibition constants in the range of 21–129 nM gainst hCA II, and 23–79 nM against hCA IX, respectively). The new bis-sulfonamides also showed inhibition of growth of several tumor cell lines (ex vivo), with GI₅₀ values in the range of 0.74–10.0 μg/mL against the human colon cancer cell line HCT116, the human lung cancer cell line H460 and the human breast cancer cell line MCF-7.     

Influence of side-chain changes on histone deacetylase inhibitory and cytotoxicity activities of curcuminoid derivatives

Using curcuminoids as lead compounds, fifty-nine curcuminoid derivatives with different side chains at the phenolic moiety were synthesized. All compounds were investigated for their histone deacetylase (HDAC) inhibitory activities. The potent pan-HDAC inhibitors were further tested against three human cancer cell lines including Hela, HCT116 and MCF-7 with MTT-based assay. The bisethylamide 4z and the mono-sec-butyl derivative 5j manifested good antiproliferative activities against HCT116 cancer cells with the IC₅₀ values as 14.60 ± 1.19 μg/mL and 7.33 ± 0.98 μg/mL, respectively. Molecular docking study of both compounds with Class I HDACs revealed that the compounds might bind tightly to the binding pocket of HDAC2. These findings suggested that these compounds can be putative candidates for the development of anticancer drugs via inhibiting HDACs.     

Primaquine homodimers as potential antiplasmodial and anticancer agents

Primaquine homodimers, e.g. symmetric PQ-diamides of dicarboxylic acids containing 4 to 8 carbon atoms, were evaluated against Plasmodium berghei hepatic stages and P. falciparum blood stages, as well as against three cancer cell lines. Novel PQ-homodimers exerted much higher activity against hepatic stages, but less pronounced activity against blood stages in comparison to the parent drug. The submicromolar activity of succinic, fumaric and maleic derivatives against P. berghei was determined (IC₅₀ values: 726.2, 198.1 and 358.4 nM, respectively). Our results indicated that the length and type of spacer between two PQ moieties highly modified the antiproliferative activities of PQ-homodimers. The general antiproliferative activity of the adipic and mesaconic derivatives against three cancer cell lines (MCF-7, HCT116, H 460) was observed (GI₅₀ = 1.78–13.7 and 2.36–4.31 µM, respectively), but adipic derivative was less toxic to human embryonic kidney cells (HEK 293). High selectivity of fumaric and suberic derivatives against breast adenocarcinoma cell line MCF-7 was detected. These two compounds have shown no antiproliferative activity against other tumor cells and HEK 293.     

5-((1-Aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones as potential anticancer agents with anti-inflammatory properties

A series of novel 5-((1-aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones (3a–z) have been evaluated for in vitro cytotoxicity against a panel of 60 human tumor cell lines. Compound 3k exhibited the most potent growth inhibition against melanoma MDA-MB-435 cells (GI₅₀ = 850 nM), against leukemia SR cancer cells (GI₅₀ = 1.45 μM), and OVCAR-3 (GI₅₀ = 1.26 μM) ovarian cancer cell lines. The structurally related compound 3s had a GI₅₀ value of 1.77 μM against MDA-MB-435 cells. The N-naphthoyl analogue 3t had GI₅₀ values of 1.30 and 1.91 μM against HOP-92 non-small cell lung cancer and MDA-MB-435 melanoma cell lines, respectively. The related analogue 3w had GI₅₀ values of 1.09 μM against HOP-92 non-small cell lung cancer cell lines. Interestingly, docking of the two active molecules 3k and 3w into the active site of COX-2 indicates that these compounds are COX-2 ligands with strong hydrophobic and hydrogen bonding interactions. Thus, compounds 3k, 3t, 3s, and 3w constitute a new class of anticancer/anti-inflammatory agents that may have unique potential for cancer therapy.     

Cytotoxic abietane-derivative diterpenoids of Salvia lachnostachys

A bioassay-guided fractionation of Salvia lachnostachys Benth leaf extract led to the isolation of three known diterpenes, namely fruticuline A (1), fruticuline B (2) and 7,20-dihydrofruticuline A (3), together with two new compounds, 4 and 5. The structures were mainly elucidated by 1D and 2D NMR spectroscopy and HRESIMS. The cytotoxic activity of the crude ethanol extract, the semi-purified fractions (A-E) and compounds 1, 2 and 4 were evaluated against seven human cancer cell lines and the normal cell line HaCat. The ethanol extract showed activity against all tested cell lines (GI₅₀ 25.0⿿44.0 μg/mL). Among the fractions, the greatest activity was exhibited by fraction A (eluted with hexane), which inhibited the growth of all tested cell lines with GI₅₀ of 3.9⿿19.5 μg/mL. Compounds 1 and 4 were the most active, inhibiting the growth of U251, MCF-7, NCI-ADR/RES, 786.0, NCI-H460, PC-3, OVCAR-03 and HaCat cell lines with GI₅₀ < 10 μM. Compound 2 showed moderate activity against MCF-7, NCI-H460, OVCAR-03, K562 and HaCat, with GI₅₀ varying 19.9⿿29.3 μM.     

Synthesis and evaluation of modified chalcone based p53 stabilizing agents

Tumor suppressor protein p53 induces cell cycle arrest and apoptotic cell death in response to various cellular stresses thereby preventing cancer development. Activation and stabilization of p53 through small organic molecules is, therefore, an attractive approach for the treatment of cancers retaining wild-type p53. In this context, a series of nineteen chalcones with various substitution patterns of functional groups including chloro, fluoro, methoxy, nitro, benzyloxy, 4-methyl benzyloxy was prepared using Claisen-Schmidt condensation. The compounds were characterized using NMR, HRMS, IR and melting points. Evaluation of synthesized compounds against human colorectal (HCT116) and breast (CAL-51) cancer cell lines revealed potent antiproliferative activities. Nine compounds displayed GI₅₀ values in the low micromolar to submicromolar range; for example (E)-1-phenyl-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (SSE14108) showed GI₅₀ of 0.473 ± 0.043 µM against HCT116 cells. Further analysis of these compounds revealed that (E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (SSE14105) and (E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (SSE14106) caused rapid (4 and 8-h post-treatment) accumulation of p53 in HCT116 cells similar to its induction by positive control, Nutlin-3. Such activities were absent in 3-(4-methoxyphenyl)propiophenone (SSE14106H2) demonstrating the importance of conjugated ketone for antiproliferative and p53 stabilizing activity of the chalcones. We further evaluated p53 levels in the presence of cycloheximide (CHX) and the results showed that the p53 stabilization was regulated at post-translational level through blockage of its degradation. These chalcones can, therefore, act as fragment leads for further structure optimization to obtain more potent p53 stabilizing agents with enhanced anti-proliferative activities.     

Synthesis,biological evaluation,and physicochemical property assessment of 4-substituted 2-phenylaminoquinazolines as Mer tyrosine kinase inhibitors

Current results identified 4-substituted 2-phenylaminoquinazoline compounds as novel Mer tyrosine kinase (Mer TK) inhibitors with a new scaffold. Twenty-one 2,4-disubstituted quinazolines (series 4–7) were designed, synthesized, and evaluated against Mer TK and a panel of human tumor cell lines aimed at exploring new Mer TK inhibitors as novel potential antitumor agents. A new lead, 4b, was discovered with a good balance between high potency (IC₅₀ 0.68 μM) in the Mer TK assay and antiproliferative activity against MV4-11 (GI₅₀ 8.54 μM), as well as other human tumor cell lines (GI₅₀ < 20 μM), and a desirable druglike property profile with low log P value (2.54) and high aqueous solubility (95.6 μg/mL). Molecular modeling elucidated an expected binding mode of 4b with Mer TK and necessary interactions between them, thus supporting the hypothesis that Mer TK might be a biologic target of this kind of new active compound.     

Antimicrobial,Antiproliferative Effects and Docking Studies of Methoxy Group Enriched Coumarin-Chalcone Hybrids

Methoxy group enriched eight coumarin-chalcone hybrid derivatives were synthesized. Antimicrobial/ antiproliferative activities were tested against eight human pathogenic microorganisms and four cancer cell lines (AGS, HepG2, MCF-7 and PC-3), respectively. Antimicrobial results showed that most of the compounds were almost more active than used standard antibiotics. Cytotoxicity results showed that 2,3,4-trimethoxyphenyl and thiophene containing structures have promising antiproliferative effects against AGS gastric cell lines with ∼5 μg/ml IC₅₀ values. At the same time, 2,4-dimethoxyphenyl bearing derivative exhibited the lowest IC₅₀ values against HepG2 (∼10 μg/ml) and PC-3 (∼5 μg/ml) cell lines. Particularly, the cell viabilities of MCF-7 cell lines were remarkably inhibited by all the compounds with lower IC₅₀ values. Therefore, molecular docking studies between hybrid ligands and quinone reductase-2 enzyme (regulates in MCF-7 cancer cells) were performed. The results demonstrated that all the derivatives can smoothly interact with interested enzyme in agreement with the experimental results. Finally, ADME parameters were studied to reveal drug-likeness potentials of the coumarin-chalcone hybrids.     

Synthesis and in vitro screening of novel N-benzyl aplysinopsin analogs as potential anticancer agents

A series of novel substituted (Z)-5-((1-benzyl-1H-indol-3-yl)methylene)imidazolidin-2,4-diones (3a-f) and (Z)-5-((1-benzyl-1H-indol-3-yl)methylene)-2-iminothiazolidin-4-ones (3g-o) have been synthesized utilizing microwave irradiation. These analogs were evaluated for in vitro cytotoxicity against a panel of 60 human tumor cell lines. Compound 3i exhibits potent growth inhibition against melanoma UACC-257 (GI₅₀ = 13.3 nM) and OVCAR-8 ovarian (GI₅₀ = 19.5 nM) cancer cells while possessing significant cytotoxicity (LC₅₀ = 308 nM and LC₅₀ = 851 nM, respectively) against the same cell lines within this series of compounds. A second analog, 3a, had GI₅₀ values of 307 and 557 nM against SK-MEL-2 melanoma and A498 renal cancer cell lines, and exhibited GI₅₀ values ranging from 0.30 to 6 μM against 98% of all cancer cell lines in the 60-cell panel. Thus, (Z)-5-((5-chloro-1-(4-fluorobenzyl)-1H-indol-3-yl)methylene)-2-iminothiazolidin-4-one (3i) and (Z)-methyl 1-(4-cyanobenzyl)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)-1H-indole-6-carboxylate (3a) can be regarded as useful lead compounds for further structural optimization as antitumor agents.     

Design,Synthesis and Structure-Activity Relationship Studies of Novel Survivin Inhibitors with Potent Anti-Proliferative Properties

The anti-apoptotic protein survivin is highly expressed in most human cancer cells, but has very low expression in normal differentiated cells. Thus survivin is considered as an attractive cancer drug target. Herein we report the design and synthesis of a series of novel survivin inhibitors based on the oxyquinoline scaffold from our recently identified hit compound UC-112. These new analogs were tested against a panel of cancer cell lines including one with multidrug-resistant phenotype. Eight of these new UC-112 analogs showed IC₅₀ values in the nanomole range in anti-proliferative assays. The best three compounds among them along with UC-112 were submitted for NCI-60 cancer cell line screening. The results indicated that structural modification from UC-112 to our best compound 4g has improved activity by four folds (2.2 μM for UC-112 vs. 0.5 μM for 4g, average GI₅₀ values over all cancer cell lines in the NCI-60 panel).Western blot analyses demonstrated the new compounds maintained high selectivity for survivin inhibition over other members in the inhibition of apoptosis protein family. When tested in an A375 human melanoma xenograft model, the most active compound 4g effectively suppressed tumor growth and strongly induced cancer cell apoptosis in tumor tissues. This novel scaffold is promising for the development of selective survivin inhibitors as potential anticancer agents.     

Synthesis and biological evaluation of podophyllotoxin congeners as tubulin polymerization inhibitors

A series of new podophyllotoxin derivatives containing structural modifications at C-7, C-8, and C-9 were synthesized and evaluated for their cytotoxic activity against three human cancer cell lines. All the synthesized compounds showed significant growth inhibition with GI₅₀ values in micromolar levels while some of the compounds were several times more potent against MCF-7 and HeLa cell lines than MIAPACA cell line. Three compounds (12a, 12d and 12e) emerged as potent compounds with broad spectrum of cytotoxic activity against all the tested cell lines with GI₅₀ values in the range of 0.01–2.1 μM. These compounds induce microtubule depolymerization and arrests cells at the G2/M phase of the cell cycle. Moreover, compounds 12d and 12e disrupted microtubule network and accumulated tubulin in the soluble fraction in a similar manner to their parent podophyllotoxin scaffold. In addition, structure activity relationship studies within the series were also discussed. Molecular docking studies of these compounds into the colchicine-binding site of tubulin, revealed possible mode of inhibition by these compounds.     

Cytotoxic,larvicidal, nematicidal,and antifeedant activities of piperidin-connected 2-thioxoimidazolidin-4-one derivatives

The objective of this study was to investigate brine shrimp cytotoxicity, larvicidal, nematicidal, and antifeedant activities of novel piperidin-connected 2-thioxo-imidazolidin-4-one derivatives. The activities of target compounds were compared with some naturally occurring (?)-pinidinol, hydantocidin, and positive controls. Target compounds were synthesized via cyclocondensation method. The compounds were synthesized and then characterized by infrared spectroscopy, ¹H NMR, ¹³C NMR, mass spectral, and elemental analyses. Brine shrimp cytotoxicity assay was investigated using freshly hatched, free-swimming nauplii of Artemiasalina. Larvicidal screening was performed against urban mosquito larvae (Culex quinquefasciatus). Nematicidal activity was evaluated using juvenile nematodes of Meloidogyne javanica. Regarding antifeedant activity, marine-acclimated Oreochromis mossambicus fingerlings were used. Compounds 3a-c (piperidin-connected 2-thioxoimidazolidin-4-one) were found to be lethal to the second instar larvae of mosquito, which produced LD₅₀ values of 1.37, 6.66, 6.51 μg/mL, compared to compounds (?) pinidinol and hyantocidin LD₅₀ values of 18.28 and 22.11 μg/mL respectively. Compound 3a-c was found to kill 100% of fish fingerlings within 6 h at 20 µg/mL, with LD₅₀ values of 1.54, 1.79, 1.52 µg/mL, compared to compounds (?) pinidinol and hyantocidin with LD₅₀ values of 10.21 and 21.05 μg/mL respectively. Compound 3c with LD₅₀ value of 1.57 μg/mL demonstrated high nematicidal activity compared to compound 3a, 3b, (?) Pinidinol and Hyantocidin LD₅₀ values of 6.45, 2.42, 14.25, 26.30 μg/mL respectively. Therefore, the 2-thioxoimidazolidin-4-one with piperidin ring showed high potential cytotoxic, larvicidal, nematicidal, and antifeedent activities.     

Synthesis and anti-proliferative activity of aromatic substituted 5-((1-benzyl-1H-indol-3-yl)methylene)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione analogs against human tumor cell lines

Based on previous SAR studies on N-benzylindole and barbituric acid hybrid molecules, we have synthesized a series of aromatic substituted 5-((1-benzyl-1H-indol-3-yl)methylene)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione analogs (3a–i) and evaluated them for their in vitro growth inhibition and cytotoxicity against a panel of 60 human tumor cell lines. Compounds 3c, 3d, 3f and 3g were identified as highly potent anti-proliferative compounds against ovarian, renal and breast cancer cell lines with GI₅₀ values in low the nanomolar range. The 4-methoxy-N-benzyl analog (3d) was the most active compound with GI₅₀ values of 20 nM and 40 nM against OVCAR-5 ovarian cancer cells and MDA-MB-468 breast cancer cells, respectively. Two other analogs, 3c (the 4-methyl-N-benzyl analog) and 3g (the 4-fluoro-N-benzyl analog) exhibited equimolar potency against MDA-MB-468 cells GI₅₀ = 30 nM). Analog 3f (the 4-chloro-N-benzyl analog) exhibited a GI₅₀ value of 40 nM against renal cancer cell line A498. These results suggest that aromatic substituted N-benzylindole dimethylbarbituric acid hybrids may have potential for development as clinical candidates to treat a variety of solid tumors.     

Synthesis,Characterization, and Biological Study of 3-Trifluoromethylpyrazole Tethered Chalcone-Pyrrole and Pyrazoline-Pyrrole Derivatives

The present study illustrates the design and synthesis of new series of 3-trifluoromethylpyrazole tethered chalcone-pyrrole and pyrazoline-pyrrole derivatives. All compounds were further screened for in vitro cytostatic activities on full NCI 60 cancer cell lines at National Cancer Institute, USA. Compounds (2E)-3-(1H-pyrrol-2-yl)-1-{4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}prop-2-en-1-one ( 5a ) and (2E)-1-{3-methyl-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3-(1H-pyrrol-2-yl)prop-2-en-1-one ( 5c ) displayed significant antiproliferative activity (Growth Percentage: −77.10 and −92.13, respectively at 10 μM concentration) against the UO-31 cell lines from renal cancer and were further selected for assay at 10-fold dilutions of five different concentrations (10⁻⁴ to 10⁻⁸ M). Both compounds 5a and 5c exhibited promising antiproliferative activity (GI₅₀: 1.36 to 0.27 μM) against leukemia cancer cell lines HL-60 and RPMI-8226, colon cancer cell lines KM-12; breast cancer cell lines BT-549. Moreover, both compounds 5a and 5c were found to be non-cytotoxic (LC₅₀>100) against HL-60, RPMI-8226, and KM-12 cell lines. Remarkably, GI₅₀ values of compounds 5a and 5c were identified as more promising than sunitinib against most cancer cell lines. In silico study of compounds 5a and 5c exemplified the desired ADME properties for drug-likeness as well as tighter interactions with VEGFR-2. Hence, compounds 5a and 5c would be good cytotoxic agents after further clinical study.     

Synthesis,Antiproliferative and Cytotoxic Activities,DNA Binding Features and Molecular Docking Study of Novel Enamine Derivatives

Novel enamine derivatives were synthesized from the reaction of lactone and chalcones and their antiproliferative and cytotoxic activities against six cancer cell lines (e. g., HeLa, HT29, A549, MCF7, PC3 and Hep3B) and one normal cell lines (e. g., FL) were investigated along with their mode of interactions with CT‐DNA. Most of the enamine derivatives with IC₅₀ values of 86–168 μM demonstrated much stronger antiproliferative activity than the starting molecules against the cancer cells. While, among the enamine derivatives, four compounds displayed higher cytotoxic potency than the control drugs (5‐fluorouracil and cisplatin) against the Hep3B cell lines, these compounds did not exhibit any significant toxicity against normal cells, FL. The UV/VIS spectral data suggest that eight compounds cause hypochromism with a slight bathochromic shift (～6 nm), indicating that they bind to the DNA by way of an intercalative or minor groove binding mode. The binding constants of the compounds are in the range of 0.1×103 M^?1–2.3×104 M^?1. The antiproliferative activity of studied enamine derivatives could possibly be due to their DNA binding as well as their cytotoxic properties. In addition to these assays, the chalcones and enamine derivatives were investigated by molecular docking to calculate the synergistic effect of antiproliferative activities against six human cancer cell lines.     

Synthesis and anticancer activity of new thiazolo[3,2-a]pyrimidines: DNA binding and molecular modeling study

A novel series of nitrogenous heterocycles starting from chalcones including thiazolo[3,2-a]pyrimidines (20–67), were synthesized. Structure elucidation of the synthesized compounds was attained by the use of ¹H NMR, ¹³CC NMR, and Mass spectrometry. The obtained compounds were evaluated for their in vitro anticancer activity at the National Cancer Institute (NCI) 60 cell lines panel assay. Three cell lines, non-small cell lung cancer Hop-92, ovarian cancer IGROV1, and melanoma SK-MEL-2, exhibited some sensitivity against most of the tested compounds. Six compounds have passed the 5-log dose level NCI assay. Compounds 34 and 24 proved to be the most active derivatives with GI₅₀, TGI, LC₅₀ of 5.89, 20.0, 66.1% and 5.0, 19.5, 52.5% respectively. Compounds 36, 39, 63 showed lesser activity with GI₅₀, TGI, LC₅₀ 3.2, 11.8, 38.9%, 3.4, 16.6, 60.3%, 3.5, 17.8, 66.1% respectively. DNA binding assay of synthesized compound were performed. Molecular docking showed that compounds 34, 42, and 60 could effectively fit into the minor groove and selectively bind with AT base pairs. The results could confer the anticancer activity of compounds 24, 34, 36, and 39 in vitro to their abilities to bind at DNA minor groove.     

Anti-cancer activity of carbamate derivatives of melampomagnolide B

Melampomagnolide B (MMB) is a natural sesquiterpene structurally related to parthenolide (PTL). We have shown that MMB exhibits anti-leukemic properties similar to PTL. Unlike PTL, the presence of a primary hydroxyl group in the MMB molecule allows the opportunity for examining the biological activity of a variety of conjugated analogs of MMB. We have now synthesized a series of carbamate analogs of MMB and evaluated these derivatives for anti-cancer activity against a panel of sixty human cancer cell lines. Analogs 6a and 6e exhibited promising anti-leukemic activity against human leukemia cell line CCRF-CEM with GI₅₀ values of 680 and 620 nM, respectively. Analog 6a also showed GI₅₀ values of 1.98 and 1.38 μM respectively, against RPMI-8226 and SR leukemia cell lines and GI₅₀ values of 460 and 570 nM against MDA-MB-435 melanoma and MDA-MB-468 breast cancer cell lines, respectively. Analog 6e had GI₅₀ values of 650 and 900 nM against HOP-92 non-small cell lung and RXF 393 renal cancer cell lines.     

Synthesis of novel pyrazolic analogues of chalcones and their 3-aryl-4-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)-1-phenyl-1H-pyrazole derivatives as potential antitumor agents

Novel (E)-1-aryl-3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)prop-2-en-1-ones 5/6 (pyrazolic chalcones) were synthesized from a Claisen–Schmidt reaction of 3-aryl-1-phenylpyrazol-4-carboxaldehydes 4 with several acetophenone derivatives 1. Subsequently, the microwave-assisted cyclocondensation reaction of chalcones 5/6 with hydrazine afforded the new racemic 3-aryl-4-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)-1-phenyl-1H-pyrazoles 7 or their N-acetyl derivatives 8 and 9 when reactions where carried out in DMF or acetic acid, respectively. Several of these compounds were screened by the US National Cancer Institute (NCI) for their ability to inhibit 60 different human tumor cell lines, where 5c and 9g showed remarkable activity mainly against leukemia (K-562 and SR), renal cancer (UO-31) and non-small cell lung cancer (HOP-92) cell lines, with the most important GI₅₀ values ranging from 0.04 to 11.4 μM, from the in vitro assays.