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Abstract: Certain 3-phenylquinolinylchalcone derivatives were synthesized and evaluated for their antiproliferative activities. Among them, (E)-3-(3-(4-methoxyphenyl)quinolin-2-yl)-1-phenylprop-2-en-1-one (6a) and (E)-1-(5-bromothiophen-2-yl)-3-(3-(4-methoxyphenyl)quinolin-2-yl)prop-2-en-1-one (11) were identified as potential lead compounds for further development. Compound 6a was active against the growth of H1299 and SKBR-3 with IC50 values of 1.41 and 0.70 μM respectively which was more active than the positive topotecan (IC50 values of 6.02 and 8.91 μM respectively). Compound 11 exhibited an IC50 value of less than 0.10 μM against the growth of MDA-MB231, and non-cytotoxic to the normal mammary epithelial cell (H184B5F5/M10). Mechanism studies indicated that compound 11 induced cell cycle arrest at G2/M phase followed by activation of caspase-3, cleavage of PARP, and consequently caused the cell death. [Copyright &y& Elsevier]

Abstract: Certain iminonaphtho[2,3-b]furan derivatives were synthesized from their respective carbonyl precursors in the regiospecific and the stereospecific manners. These compounds were evaluated for their antiproliferative effects against four human carcinoma cells (MCF7, NCI-H460, SF-268, and K562) and the normal fibroblast cell line (Detroit 551). Among them, (Z)-4-(hydroxyimino)naphtho[2,3-b]furan-9(4H)-one (8) and (Z)-4-methoxy-iminonaphtho[2,3-b]furan-9(4H)-one (9) exhibited GI50 values of 0.82 and 0.60μM, respectively, against the growth of K562 cells and were inactive against the normal fibroblast Detroit 551. The selectivity index (SI) on K562 cell for 8 and 9 was >121.95 and >166.67, respectively, which is comparable to daunorubicin (SI=239) and is more favorable than camptothecin (SI=16.5). The cell cycle analysis on K562 indicated that these compounds arrest the cell cycle at the G2/M phase. The morphological assessment and DNA fragmentation analysis indicated that 9-induced cell apoptosis in K562 cells. The apoptotic induction may through caspase-3 activity and cleavage of PARP. [Copyright &y& Elsevier]

Abstract: The present report describes the synthesis and antiproliferative evaluation of certain indolo[3,2-c]quinoline derivatives. For the C6 anilino-substituted derivatives, (11H-indolo[3,2-c]quinolin-6-yl)phenylamine (6a) was inactive. Structural optimization of 6a by the introduction of a hydroxyl group at the anilino-moiety resulted in the enhancement of antiproliferative activity in which the activity decreased in an order of para-OH, 7a > meta-OH, 8a > ortho-OH, 9a. For the C6 alkylamino-substituted derivatives, 11a, 12a, 13a, 14a, and 15a exhibited comparable antiproliferative activities against all cancer cells tested and the skin Detroit 551 normal fibroblast cells. Three cancer cells, HeLa, A549, and SKHep, are very susceptible with IC50 of less than 2.17μM while PC-3 is relatively resistant to this group of indolo[3,2-c]quinolines. For the 2-phenylethylamino derivatives, compound 20a is active against the growth of HeLa with an IC50 of 0.52μM, but is less effective against the growth of Detroit 551 with an IC50 of 19.32μM. For the bis-indolo[3,2-c]quinolines, N,N-bis-[3-(11H-indolo[3,2-c]quinolin-6-yl)aminopropyl]amine hydrochloride (25) is more active than its N-methyl derivative 26 and the positive Doxorubicin. Mechanism studies indicated 25 can induce caspase-3 activation, γ-H2AX phosphorylation, cleavage of poly(ADP-ribose)polymerase and DNA fragmentation. These results provide evidence that DNA, topo I, and topo II are the primary targets of indolo[3,2-c]quinoline derivatives and that consequently inhibits proliferation and causes apoptosis in cancer cells. [Copyright &y& Elsevier]

Abstract: A number of 6-arylindeno[1,2-c]quinoline derivatives were synthesized and evaluated for their antiproliferative activities against the growth of five cancer cell lines including human hepatocelluar carcinoma (Hep G2, Hep 3B and Hep2.2.1), non-small cell lung cancer (A549 and H1299), and normal diploid embryonic lung cell line (MRC-5). The preliminary results indicated that 9-(3-(dimethylamino)propoxy)-6-(4-(3-(dimethylamino)propoxy)phenyl)-2-fluoro-11H-indeno[1,2-c]quinolin-11-one (14c) was the most potent with GI50 values of 0.61, 0.67, 0.59, and 0.72μM against the growth of Hep G2, Hep 3B, Hep 2.2.1, and H1299 cells, respectively. Results have also shown that 2,9-bis(3-(dimethylamino)propoxy)-6-(4-(3-(dimethylamino)propoxy)phenyl)-11H-indeno[1,2-c]quinolin-11-one (17), which exhibited GI50 of 0.60 and 0.68μM against the growth of Hep G2 and A549, respectively, was more active than the positive topotecan and irinotecan. Compound 17 was less toxic than topotecan against the growth of normal cell (MRC-5) and therefore, was selected for further evaluation. Results indicated that compound 17 induce cell cycle arrest in G2/M phase, DNA fragmentation, and disrupt the microtubule network in A549 cells. The apoptotic induction may through the cleavage of PARP. [Copyright &y& Elsevier]

Abstract: We report herein the synthesis and anti-osteoporotic evaluation of certain 3-amino-2-hydroxypropoxyisoflavone derivatives. The results indicated that 3-(3,4-dimethoxyphenyl)-7-(oxiran-2-ylmethoxy)-4H-chromen-4-one (4) and 3-{4-[3-(cyclohexylamino)-2-hydroxypropoxy]phenyl}-7-methoxy-4H-chromen-4-one (5a) exhibited significant inhibitory effects on osteoclast activity (TRAP activity in RAW 264.7 with an ED50 of 0.56 and 2.28μM respectively). Both compounds have also exhibited very strong osteogenic effects, approximately a 10-fold effect of Ipriflavone on mineralization of osteoblasts (MC3T3E1 cells, a preosteoblast cell line derived from calvaria of C57BL/6 mice). Results indicated the potency on enhancing mineralization in D1 cells (a bone marrow mesenchymal cell line derived from BALB/c mice) decreased in an order 4 >Ipriflavone> 5a. However, the potency on enhancing mineralization in human adipose tissue derived stem cells (hADSCs) decreased in an order 5a > 4 >Raloxifene>Ipriflavone. Compound 5a has been found to be non-cytotoxic and especially active in the enhancement of mineralization in human adipose tissue derived stem cells. Therefore, 5a was selected as a potential lead for further structural optimization. [Copyright &y& Elsevier]

Certain indolo-, pyrrolo-, and benzofuro-quinolin-2(1H)-ones 4a,b, 6, 8, 16a–c and 6-anilinoindoloquinoline derivatives 10a,b, 11a,b, 12a,b have been synthesized and evaluated in vitro against a 3-cell lines panel consisting of MCF7 (Breast), NCI-H460 (Lung), and SF-268 (CNS). Those active compounds 4a,b, 6, 8, 10a,b, 11a,b, 12a,b were then evaluated in the full panel of 60 human tumor cell lines derived from nine cancer cell types. The results have shown that cytotoxicity decreases in the order of 6-anilinoindoloquinolines>indoloquinolin-2(1H)-ones>pyrroloquinolin-2(1H)-ones>benzofuroquinolin-2(1H)-ones. Among them, 1-[3-(11H-indolo[3,2-c]quinolin-6ylamino)phenyl]ethanone oxime hydrochloride (11a) and its 2-chloro derivative (11b) were most active, with mean GI50 values of 1.70 and 1.35 μM, respectively. Both compounds 11a,b were also found to inhibit the growth of SNB-75 (CNS cancer cell) with a GI50 value of less than 0.01 μM, and, therefore, were selected for further evaluation for in vivo antitumor activity. [Copyright &y& Elsevier]

Abstract: A facile three-step synthetic route toward 1,3-diaryl-1H-benzo[g]indazoles 1a–1n starting with 3,4-dimethoxy-2-allylbenzaldehyde (6) in modest total yield is described. The facile route was carried by aldol condensation of aldehyde 6 with aryl methyl ketones 5a–5d in alkaline MeOH at reflux, Knorr pyrazole synthesis of the resulting chalcones 4a–4d with aryl hydrazines 3a–3e in EtOH at reflux followed by DDQ-mediated aromatization in toluene at reflux, and oxidative cleavage annulation of olefins 2a–2n with the one-pot combination of OsO4/NaIO4/HOAc in the aqueous THF at reflux. [Copyright &y& Elsevier]

Abstract: A new method for synthesis of rodocaine (1) is presented. Two key steps were carried out by the N-bromosuccinimide (NBS)-mediated intermolecular addition of known enamine 5 with allyltrimethyl silane in presence of boron trifluoride etherate (BF3/OEt2) and the intramolecular ring-closing metathesis of triene 3. The Diels–Alder cycloaddition of triene 3 with different ethyl propiolates was also studied. [Copyright &y& Elsevier]

Abstract: A novel method for the synthesis of 3-N-substituted 4-aryl-1,2,3,6-tetrahydropyridine 3 is presented. The process is carried out by the allylic bromination of 4-aryl-1,2,3,6-tetrahydropyridines 1 with N-bromosuccinimide in propanoic acid and palladium-catalyzed cross coupling of the corresponding bromide 2 with different N-based nucleophiles. [ABSTRACT FROM AUTHOR]

Abstract: An easy and straightforward synthesis of spiroindenyl heterocycles by the repeated treatment of boron trifluoride etherate (BF3-OEt2) is reported. The overall transformation from ketones 1 to spiro-fused indenes 3 proceeds via Wittig olefination, deconjugation, Grignard addition, and intramolecular electrophilic cyclization in moderate yields. It presents a novel rearrangement reaction catalyzed by boron trifluoride etherate and broadens the scope of application. [Copyright &y& Elsevier]

Abstract: A series of 11-alkoxylated and 11-aminated benzofuro[2,3-b]quinoline derivatives were designed, synthesized, and evaluated for their anti-TB and cytotoxic activities. The known 11-chlorobenzofuro[2,3-b]quinoline (3) was synthesized in a single step from anthranilic acid and 2-coumaranone in phosphorus oxychloride in 51% yield for the first time. Treatment of 3 with alcohols and amines gave 11-alkoxylated and 11-aminated benzofuro[2,3-b]quinoline derivatives respectively, which were evaluated for their anti-TB and cytotoxic activities. Our results indicated that 11-arylaminated derivatives were more active than their respective 11-aryloxylated isosteric isomers against Mycobacterium tuberculosis. Among the tested compounds, 11-methoxybenzofuro[2,3-b]quinoline (4), 11-methylamino- benzofuro[2,3-b]quinoline (9), and 11-dimethylaminobenzofuro[2,3-b]quinoline (14) exhibited significant activities against the growth of M. tuberculosis (MIC values of <0.20μg/mL) and low cytotoxicities against VERO cell with IC50 values of 11.77, 5.55, and >30.00μg/mL respectively. The selectivity index (SI=IC50/MIC) for 4, 9, and 14 was greater than 58.85, 27.75, and 150 respectively. [Copyright &y& Elsevier]

Abstract: A number of 6-aryl-11-iminoindeno[1,2-c]quinoline derivatives were synthesized and evaluated for their antiproliferative activities. Among them, (E)-6-{4-[3-(dimethylamino)propoxy]phenyl}-2-fluoro-9-hydroxy-11H-indeno[1,2-c]quinolin-11-one O-3-(dimethylamino)propyl oxime (23a) was the most active, exhibited GI50 values of 0.64, 0.39, 0.55, 0.67, and 0.65μM against the growth of Hep G2, Hep 3B, A549, H1299, and MDA-MB-231, respectively. Compound 23a inhibited the growth of hepatoma cell lines in a dose- and time-dependent manner. The proportion of cells was decreased in the G1 and accumulated in G2/M phase after 12h treatment of 23a, while the hypodiploid (sub-G0/G1 phase) cells increased. Further investigations have shown that 23a induced cell cycle arrest at G2/M phase and induce apoptosis via activation of p53, Bax, and caspase-8 which consequently cause cell death. [Copyright &y& Elsevier]

Abstract: Synthesis and anti-inflammatory effects of certain furo[3′,2′:3,4]naphtho[1,2-d]imidazole derivatives 12–18 were studied. These compounds were synthesized from naphtho[1,2-b]furan-4,5-dione (10) which in turn was prepared from the known 2-hydoxy-1,4-naphthoquinone (7) in a one pot reaction. Furo[3′,2′:3,4]naphtho[1,2-d]imidazole (12) was inactive (IC50 value of >30μM) while its 5-phenyl derivative 13, with an IC50 value of 16.3 and 11.4μM against lysozyme and β-glucuronidase release, respectively, was comparable to the positive trifluoperazine. The same potency was observed for 5-furan derivative 16 with an IC50 value of 19.5 and 11.3μM against lysozyme and β-glucuronidase release, respectively. An electron-withdrawing NO2 substituted on 5-phenyl or 5-furanyl group led to the devoid of activity as in the cases of 14 and 17. Among them, compound 15 exhibited significant inhibitory effects, with an IC50 value of 7.4 and 5.0μM against lysozyme and β-glucuronidase release, respectively. For the LPS-induced NO production, the phenyl derivatives 12–15 were inactive while the nitrofuran counterparts 17 and 18 suppress LPS-induced NO production significantly, with an IC50 value of 1.5 and 1.3μM, respectively, which are more active than that of the positive 1400W. Compounds 16–18 were capable of inhibiting LPS-induced iNOS protein expression at a dose-dependent manner in which compound 18, with an IC50 of 0.52μM in the inhibition of iNOS expression, is approximately fivefold more potent than that of the positive 1400W. In the CLP rat animal model, compound 18 was found to be more active than the positive hydrocortisone in the inhibition of the iNOS mRNA expression in rat lung tissue. The sepsis-induced PGE2 production in rat serum decreased 150% by the pretreatment of 18 in a dose of 10mg/kg. [Copyright &y& Elsevier]