Combination of 4-anilinoquinazoline,arylurea and tertiary amine moiety to discover novel anticancer agents

In present study, 4-anilinoquinazolines scaffold, arylurea and tertiary amine moiety were combined to design, synthesize gefitinib analogs and discover novel anticancer agents. A series of 4-anilinoquinazoline derivatives (1, 2, 3 and 4) bearing arylurea and tertiary amine moiety at its 6-position were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against A431 cell and A549 cell. The SAR of the title compounds was discussed. The compounds 2d, 2i and 2j with potent antiproliferative activities were evaluated their inhibitory activity against EGFR-TK. Compound 2j displayed potent inhibitory activity against EGFR-TK. In addition, compound 2j, at 50 mg/kg, can completely inhibit cancer growth in established nude mouse A549 xenograft model in vivo. These results suggest that the 4-anilinoquinazoline derivatives bearing diarylurea and tertiary amino moiety at its 6-position can serve as anticancer agents and EGFR inhibitors.     

Anti-proliferative effect of chalcone derivatives through inactivation of NF-κB in human cancer cells

To investigate the anti-proliferative effect of NF-κB inhibitor, a series of analogs of (E)-1-(2-hydroxy-6-(isopentyloxy)phenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (5a) were prepared and evaluated for their NF-κB inhibition and anti-proliferative activity against various human cancer cell lines. Compounds (E)-1-(2-(3,3-dimethylbutoxy)-6-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (5e) and (E)-4-(3-(2-(3,3-dimethylbutoxy)-6-hydroxyphenyl)-3-oxoprop-1-enyl)benzenesulfonamide (5p) showed good NF-κB inhibition as well as potent anti-proliferative activity. SAR studies showed that all the compounds with potent or moderate NF-κB inhibition displayed good anti-proliferative activity. All the analogs (5b–r) maintained a good correlation between their NF-κB inhibition and anti-proliferative activity though the extent is not directly proportional to each other.     

Synthesis and biological evaluation of ethacrynic acid derivatives bearing sulfonamides as potent anti-cancer agents

A series of ethacrynic acid (2-[2,3-dichloro-4-(2-methylidenebutanoyl)phenoxy]acetic acid) (EA, Edecrin) containing sulfonamides linked via three types of linkers namely 1,2-ethylenediamine, piperazine and 4-aminopiperidine was synthesized and subsequently evaluated in vitro against HL60 and HCT116 cancer cell lines. All the EA analogs, excluding 6a and 6c, showed anti-proliferative activity with IC_50s in the micromolar range (less than 4 uM). Three derivatives 6b, 7b and 7e were selected for their interesting dual activity on HL60 cell line in order to be further evaluated against a panel of cancer cell lines (HCT116, A549, MCF7, PC3, U87-MG and SKOV3) as well as on MRC5 as a normal cell line. These compounds displayed IC₅₀ values in nanomolar range against A549, MCF7, PC3 and HCT116 cell lines, deducing the discovery that piperazine or 4-aminopiperidine is the linker’s best choice to develop EA analogs with highly potent anti-proliferative activities own up to 24 nM. Besides, in terms of selectivity, those linkers are more suitable offering safety ratios of up to 63.8.     

The cytotoxicity of 8-O-4′ neolignans from the seeds of Crataegus pinnatifida

Nine new 8-O-4′ neolignans, named pinnatifidanin B I–IX (1–9), together with 9 known analogs (10–18) were isolated from the seeds of Crataegus pinnatifida. The structures of 1–18 were determined by spectroscopic methods, including 1D, 2D NMR, CD and HRESIMS analysis. Compounds 8–11, 17 and 18 displayed potent cytotoxic activities against human cancer cell lines, and most interestingly, none of the 6 compounds displayed inhibitory activity against human lung cell line (Mrc5). The 6 cytotoxic compounds are considered to be potential as antitumor agents, which could significantly inhibit the cancer cell growth in a dose-dependent manner and are probably safer than positive control drug.     

Synthesis and antibacterial activity of novel 4″-O-(1-aralkyl-1,2,3-triazol-4-methyl-carbamoyl) azithromycin analogs

Three novel structural series of 4″-O-(1-aralkyl-1,2,3-triazol-4-methyl-carbamoyl) azithromycin analogs were designed, synthesized and evaluated for their in vitro antibacterial activity. All the target compounds exhibited excellent activity against erythromycin-susceptible Streptococcus pyogenes, and significantly improved activity against three phenotypes of erythromycin-resistant Streptococcus pneumoniae compared with clarithromycin and azithromycin. Among the three series of azithromycin analogs, the novel series of 11,4″-disubstituted azithromycin analogs 9a–k exhibited the most effective and balanced activity against susceptible and resistant bacteria. Among them, compound 9j showed the most potent activity against Staphylococcus aureus ATCC25923 (0.008 µg/mL) and Streptococcus pyogenes R2 (1 µg/mL). Besides, all the 11,4″-disubstituted azithromycin analogs 9a–k except 9f shared the identical activity with the MIC value <0.002 µg/mL against Streptococcus pyogenes S2. Furthermore, compounds 9g, 9h, 9j and 9k displayed significantly improved activity compared with the references against all the three phenotypes of resistant S. pneumoniae. Particularly, compound 9k was the most effective (0.06, 0.03 and 0.125 µg/mL) against all the erythromycin-resistant S. pneumoniae expressing the erm gene, the mef gene and the erm and mef genes, exhibiting 2133, 133 and 2048-fold more potent activity than azithromycin, respectively.     

Synthesis,biological evaluation and molecular docking studies of aminochalcone derivatives as potential anticancer agents by targeting tubulin colchicine binding site

A series of aminochalcone derivatives have been synthesized, characterized by HRMS, ¹H NMR and ¹³C NMR and evaluated for their antiproliferative activity against HepG2 and HCT116 human cancer cell lines. The most of new synthesized compounds displayed moderate to potent antiproliferative activity against test cancer cell lines. Among the derivatives, compound 4 displayed potent inhibitory activity with IC₅₀ values ranged from 0.018 to 5.33 μM against all tested cancer cell lines including drug resistant HCT-8/T. Furthermore, this compound showed low cytotoxicity on normal human cell lines (LO2). The in vitro tubulin polymerization assay showed that compound 4 inhibited tubulin assembly in a concentration-dependent manner with IC₅₀ value of 7.1 μM, when compared to standard colchicine (IC₅₀ = 9.0 μM). Further biological evaluations revealed that compound 4 was able to arrest the cell cycle in G2/M phase. Molecular docking study demonstrated the interaction of compound 4 at the colchicine binding site of tubulin. All the results indicated that compound 4 is a promising inhibitor of tubulin polymerization for the treatment of cancer.     

Design and synthesis of 6,7-methylenedioxy-4-substituted phenylquinolin-2(1H)-one derivatives as novel anticancer agents that induce apoptosis with cell cycle arrest at G2/M phase

Novel 6,7-methylenedioxy-4-substituted phenylquinolin-2(1H)-one derivatives 12a–n were designed and prepared through an intramolecular cyclization reaction and evaluated for in vitro anticancer activity. Among the synthesized compounds, 6,7-methylenedioxy-4-(2,4-dimethoxyphenyl)quinolin-2(1H)-one (12e) displayed potent cytotoxicity against several different tumor cell lines at a sub-micromolar level. Furthermore, results of fluorescence-activated cell sorting (FACS) analysis suggested that 12e induced cell cycle arrest in the G2/M phase accompanied by apoptosis in HL-60 and H460 cells. This action was confirmed by Hoechst staining and caspase-3 activation. Due to their easy synthesis and remarkable biological activities, 4-phenylquinolin-2(1H)-one analogs (4-PQs) are promising new anticancer leads based on the quinoline scaffold. Accordingly, compound 12e was identified as a new lead compound that merits further optimization and development as an anticancer candidate.     

New β-lactam – Tetramic acid hybrids show promising antibacterial activities

β-Lactams are the most important class of antibiotics, for which the emergence of resistance threatens their utility. As such, we explored the extent to which the tetramic acid motif, frequently found in naturally occurring antibiotics, can be used to generate novel β-lactam antibiotics with improved antibacterial activity. We synthesized new ampicillin – tetramic acid, cephalosporin – tetramic acid, and cephamycin – tetramic acid analogs and evaluated their activities against problematic Gram-positive and Gram-negative pathogens. Amongst the analogs, a 7-aminocephalosporanic acid analog, 3397, and a 7-amino-3-vinyl cephalosporanic acid, 3436, showed potent activities against S. aureus NRS 70 (MRSA) with MICs of 6.25?μg/mL and 3.13?μg/mL respectively. These new analogs were ≥16-fold more potent than cefaclor and cephalexin. Additionally, a Δ² cephamycin – tetramic acid analog 3474 which contained a basic guanidinium substituent at the 5-position of the tetramic acid core displayed potent activity against several clinical strains of K. pneumoniae and E. coli.     

Antitumor agents 278. 4-Amino-2H-benzo[h]chromen-2-one (ABO) analogs as potent in vitro anti-cancer agents

4-Amino-2H-benzo[h]chromen-2-one (ABO) analogs were designed, synthesized, and evaluated for cytotoxic activity. Among all 4-substituted ABO analogs, cyclohexyl (12), N-methoxy-N-methylacetamide (14), and various aromatic derivatives (15–25 and 27) exhibited promising cell growth inhibitory activity with ED₅₀ values of 0.01–5.8 μM against all tested tumor cell lines. The 4′-methoxyphenyl derivative (18) and 3′-methylphenyl derivative (24) showed the most potent antitumor activity against a broad range of cancer cell lines with ED₅₀ values of 0.01–76 μM. Preliminary SAR results indicated that substitutions on nitrogen are critical to the antitumor potency.     

Synthesis,antitumor activity evaluation and mechanistic study of novel hederacolchiside A1 derivatives bearing an aryl triazole moiety

In an attempt to arrive at a more potent antitumor agent than the parent natural saponin hederacolchiside A₁, 23 hederacolchiside A₁ derivatives (4a-4w) were synthesized via Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition and screened in vitro for cytotoxicity against six human cancer cell lines. The structure-activity relationship of these compounds was elucidated, and the biological screening results showed that most of the compounds exhibited moderate to high levels of antitumor activities against the tested cell lines and some of them displayed more potent inhibitory activities compared with hederacolchiside A₁. Compound 4f showed a 2- to 7-fold more potent activity than hederacolchiside A₁. The mechanistic study of 4f revealed that this compound can induce cell apoptosis in HepG2 cells via mitochondrial-mediated intrinsic pathways.     

Design,synthesis, docking studies and biological evaluation of novel chalcone derivatives as potential histone deacetylase inhibitors

A group of novel chalcone derivatives comprising hydroxamic acid or 2-aminobenzamide group as zinc binding groups (ZBG) were synthesized. The structure of the prepared compounds was fully characterized by IR, NMR and elemental microanalyses. Most of the tested compounds displayed strong to moderate HDAC inhibitory activity. Some of these compounds showed potent anti-proliferative activity against human HepG2, MCF-7 and HCT-116 cell lines. In particular, compounds 4a and 4b exhibited significant anti-proliferative activity against the three cell lines compared to SAHA as reference drug and displayed promising profile as anti-tumor candidates. The results indicated that these chalcone derivatives could serve as a promising lead compounds for further optimization as antitumor agents.     

Tomensides A–D,new antiproliferative phenylpropanoid sucrose esters from Prunus tomentosa leaves

To search for novel cytotoxic constituents against cancer cells as lead structures for drug development, four new 3-phenylpropanoid-triacetyl sucrose esters, named tomensides A–D (1–4), and three known analogs (5–7) were isolated from the leaves of Prunus tomentosa. Their structures were elucidated by spectroscopic analyses (1D, 2D NMR, CD and HRESIMS). The cytotoxic activities of all isolates against four human cancer cell lines (MCF-7, A549, HeLa and HT-29) were assayed, and the results showed that these isolates displayed stronger inhibitory activities compared with positive control 5-fluorouracil. Tomenside A (1) was the most active compound with IC₅₀ values of 0.11–0.62 μM against the four tested cell lines. The structure–activity relationship (SAR) of the isolates was also discussed. The primary screening results indicated that these 3-phenylpropanoid-triacetyl sucrose esters might be valuable source for new potent anticancer drug candidates.     

Design,synthesis and cytotoxicity of novel 3′-N-alkoxycarbonyl docetaxel analogs

By-product 9a exhibited potent cytotoxicity against both SK-OV-3 and A549 cell lines. The structure of 9a was characterized using 1D and 2D NMR experiments and confirmed by synthesis to afford a diastereomeric mixture (16a) that was identical to 9a, as well as a pair of diastereomers (R)-16b and (S)-16c. The preliminary SAR study demonstrated that analogs with an (R)-configuration were slightly more potent than analogs with an (S)-configuration. In addition, α,α-gem-dimethyl analogs 16g–i were the most potent analogs in this series, exhibiting similar potency to docetaxel and greater potency than Taxol against the SK-OV-3 cell line. For the A549 cell line, analogs 16g–i were more potent (>65-fold) than both docetaxel and Taxol.     

Synthesis,biological evaluation and molecular docking studies of a new series of chalcones containing naphthalene moiety as anticancer agents

A series of chalcones containing naphthalene moiety 4a–4p have been synthesized, characterized by ¹H NMR and ¹³C NMR and evaluated for their in vitro anticancer activity. The majority of the screened compounds displayed potent anticancer activity against both HCT116 and HepG2 human cancer cell lines. Among the series, compound 4h with a diethylamino group at the para position of the phenyl ring exhibited the most potent anticancer activity against HCT116 and HepG2 cell lines with IC₅₀ values of 1.20 ± 0.07 and 1.02 ± 0.04 μM, respectively. The preliminary structure–activity relationship has been summarized. Tubulin polymerization experiments indicated that 4h effectively inhibited tubulin polymerization and flow cytometric assay revealed that 4h arrests HepG2 cells at the G2/M phase in a dose-dependent manner. Furthermore, molecular docking studies suggested that 4h binds to the colchicine binding site of tubulin.     

Diverse amide analogs of sulindac for cancer treatment and prevention

Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. Sulindac sulfide amide (1) possessing greatly reduced COX-related inhibition relative to sulindac displayed in vivo antitumor activity that was comparable to sulindac in a human colon tumor xenograft model. Inspired by these observations, a panel of diverse sulindac amide derivatives have been synthesized and their activity probed against three cancer cell lines (prostate, colon and breast). A neutral analog, compound 79 was identified with comparable potency relative to lead 1 and activity against a panel of lymphoblastic leukemia cell lines. Several new series also show good activity relative to the parent (1), including five analogs that also possess nanomolar inhibitory potencies against acute lymphoblastic leukemia cells. Several new analogs identified may serve as anticancer lead candidates for further development.     

Synthesis and biological evaluation of amino analogs of Ludartin: Potent and selective cytotoxic agents

Diverse amino analogs of Ludartin, a cytotoxic guaianolide and a position isomer of an anticancer drug, Arglabin were prepared through Michael type addition at its highly active α-methylene-γ-lactone motif. The semisynthetic derivatives were subjected to sulphorhodamine B cytotoxicity assay against a panel of four different human cancer cell lines viz. lung (A-549), leukemia (THP-1), prostate (PC-3) and colon (HCT-116) to look into structure–activity relationship. Few of the analogs displayed potent selective cytotoxicity compared to the parent molecule-Ludartin (1). (11R)-13-(Diethyl amine)-11,13-dihydroludartin (6) and (11R)-13-(piperidine)-11,13-dihydroludartin (10) showed almost same cytotoxicity against leukemia cell lines (THP-1) as that of parent molecule-Ludartin, but were more active against colon (HCT-116) cancer cells. (11R)-13-(Morpholine)-11,13-dihydroludartin (11) displayed selectively better cytotoxicity against Leukemia cancer cells (THP-1) exhibiting IC₅₀ of 2.8 μM. (11R)-13-(6-Nitroindazole)-11,13-dihydroludartin (17) was four times more potent than Ludartin with selective cytotoxic effects against prostate cancer cells (2.2 μM) while as (11R)-13-(6-nitroindazole)-11,13-dihydroludartin (18) exhibited three-fold selective cytotoxicity for Lung (A-549) cancer cell lines exhibiting IC₅₀ of 2.6 μM.     

Biaryl purine derivatives as potent antiproliferative agents: Inhibitors of cyclin dependent kinases. Part I

The introduction of an aryl ring onto the 4-position of the C-6 benzyl amino group of the Cdk inhibitor roscovitine (2), maintained the potent Cdk inhibition demonstrated by roscovitine (2) as well as greatly improving the antiproliferative activity. A series of C-6 biarylmethylamino derivatives was prepared addressing modifications on the C-6 biaryl rings, N-9 and C-2 positions to provide compounds that displayed potent cytotoxic activity against tumor cell lines. In particular, derivative 21h demonstrated a >750-fold improvement in the growth inhibition of HeLa cells compared to roscovitine (2).     

Aryl fluorosulfate analogues as potent antimicrobial agents: SAR,cytotoxicity and docking studies

A series of aryl fluorosulfate analogues (1–37) were synthesized and tested for in vitro antibacterial and antifungal studies, and validated by docking studies. The compounds 9, 12, 14, 19, 25, 26, 35, 36 and 37 exhibited superior antibacterial potency against tested bacterial strains, while compounds 2, 4, 5, 15, 35, 36 and 37 were found to have better antifungal activity against tested fungal strains, compared to standard antibiotic gentamicin and ketoconazole respectively. Among all the synthesized 37 analogs, compounds 25, 26, 35, 36 and 37 displayed excellent anti-biofilm property against Staphylococcus aureus. The structure–activity relationship (SAR) revealed that the antimicrobial activity depends upon the presence of –OSO₂F group and slender effect of different substituent’s on the phenyl rings. The electron donating (OCH₃) groups in analogs increase the antibacterial activity, and interestingly the electron withdrawing (Cl, NO₂, F and Br) groups increase the antifungal activity (except compound 35, 36 and 37). The mechanism of potent compounds showed membrane damage on bacteria confirmed by SEM. Compounds 35, 36 and 37 exhibited highest glide g-scores in molecular docking studies and validated the biocidal property.     

Design,synthesis, and biological evaluation of novel 1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide analogs in MCF-7 and MDA-MB-468 breast cancer cell lines

A series of novel 1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide analogs were designed and synthesized for developing pyrazinoindolone scaffolds as anti-breast cancer agents. Compounds 1h and 1i, having a furan-2-yl-methylamide and benzylamide group, respectively, exhibited more potent cytotoxicity in MDA-MB-468 triple-negative breast cancer (TNBC) cells than compounds possessing aliphatic groups. Compounds 2a and 2b, as (R)-enantiomers of 1h and 1i, also had inhibitory activity against MDA-MB-468 cells. Moreover, analogs (3a–b and 3d–e) bearing a benzyl group at the N-2 position showed more potent activity than gefitinib, as a potent EFGR-TK inhibitor. Especially, compound 3a exhibited selective cytotoxic activity against MDA-MB-468 cells; it also had a synergistic effect in combination with gefitinib against MDA-MB-468 cells. In addition, we confirmed that compounds 3a and 3d inhibit phosphorylation of Akt in MDA-MB-468 cells using western blot analysis. Therefore, these 1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide analogs may be helpful for investigating new anti-TNBC agents.     

Synthesis and SAR of novel capsazepine analogs with significant anti-cancer effects in multiple cancer types

We previously demonstrated that capsazepine (CPZ), a synthetic transient receptor potential Vanilloid subtype 1 (TRPV1) antagonist, has significant anti-cancer effects in vivo. The purpose of this study was to develop more potent analogs based upon CPZ pharmacophore and structure–activity relationships (SAR) across analogs. We generated 30 novel compounds and screened for their anti-proliferative effects in cultured HeLa cervical cancer cells. Cell viability assays identified multiple compounds with IC_50s?<?15?μM and one compound, 29 with an IC₅₀?<?5?μM; six fold more potent than CPZ. We validated the anti-proliferative efficacy of two lead compounds, 17 and 29, in vivo using HeLa-derived xenografts in athymic nude mice. Both analogs significantly reduced tumor volumes by day 8 compared to control treated animals (p?<?0.001) with no observable adverse effects. Calcium imaging determined that compound 17 activates TRPV1 whereas 29 neither activates nor inhibits TRPV1; indicating a unique mechanism-of-action that does not involve TRPV1 signaling. Cell viability assays using a panel of additional tumor types including oral squamous cell carcinoma, non-small cell lung cancer (NSCLC), breast cancer, and prostate cancer cell lines (HSC-3, H460, MDA-231, and PC-3 respectively) demonstrated that both lead compounds were efficacious against every cancer type tested. Compounds 29 displayed IC_50s of 1–2.5?μM in HSC-3and PC-3cells. Thus, we propose that these novel CPZ analogs may serve as efficacious therapeutic agents against multiple tumor types that warrant further development for clinical application.