Design,synthesis and biological evaluation of novel quinazoline derivatives as potential anti-cancer agents

Twenty-two quinazoline derivatives have been synthesised and examined for their anti-tumour activity against three tumour cell lines, namely human breast cancer cell line (MCF-7), human cervical cancer cell line (HeLa) and human hepatoma cell line (HepG2). Twelve of the tested compounds have shown promising anti-tumour activity with an IC₅₀ range of 5.0–9.7 µg/mL. Regarding the spectrum of activity, five compounds exhibited interesting anti-proliferative properties against the three tested cell lines comparable to the reference drug (dasatinib).     

Synthesis and biological evaluation of novel acylhydrazone derivatives as potential antitumor agents

We have designed, synthesized, and evaluated as potential antitumor agents a series of 2-hydroxybenzylidene derivatives of the N-(2-trifluoromethylpiridyn-4-yl)anthranilic acid hydrazide, and some analogues bearing a (2-trifluoromethyl)piridyn-4-ylamino group in 3- or 4-position of benzohydrazide or 4-position of phenylacetohydrazide. Compounds 12e, 13e, 15e, and 16e, bearing a 4-(diethylamino)salicylidene group exhibited potent cytotoxicity, with averaged GI₅₀ values in sub-micromolar range, and a variety of cell selectivity at nanomolar concentrations. The determination of acute toxicity in athymic nudes mice proved some compounds to be non-toxic, making them good candidates for further study as antitumor agents.     

Design,synthesis and evaluation of novel HDAC inhibitors as potential antitumor agents

Phenyl imidazolidin-2-one was introduced as the linker for novel HDAC inhibitors. A focused library of 20 compounds was designed and synthesized, among which eight compounds showed equivalent or higher potencies against HDAC1 as compared to vorinostat. In vitro antitumor activity assays in HCT-116, PC-3 and HL-60 cancer cells revealed six compounds with potent antitumor activities, and compound 1o showed 6- to 9-fold higher potencies compared to vorinostat. In an HCT-116 nude mice xenograft model, compound 1o displayed significant antitumor activity in both continuous and intermittent dosing schedules.     

Design and synthesis of N-phenylacetyl (sulfonyl) 4,5-dihydropyrazole derivatives as potential antitumor agents

A series of novel N-phenylacetyl (sulfonyl) 4,5-dihydropyrazole derivatives as potential telomerase inhibitors were synthesized. The bioassay tests show that compound 4a exhibited high activity against human gastric cancer cell SGC-7901, liver cancer Hep-G2 and human prostate PC-3 cell lines with IC₅₀ values of 21.23 ± 0.99, 29.43 ± 0.32 and 30.89 ± 1.07 μM, respectively. All title compounds were assayed for telomerase inhibition by a modified TRAP assay, the results show that compound 4a can inhibit telomerase with IC₅₀ value of 4.0 ± 0.32 μM. Docking simulation was performed to position compound 4a into the telomerase (3DU6) active site to determine the probable binding model.     

New analogues of AHMA as potential antitumor agents: synthesis and biological activity

A series of new analogues of 3-(9-acridinylamino)-5-hydroxymethylaniline (AHMA, 1) and AHMA-ethylcarbamate (2) were synthesized by introducing an O-alkylcarboxylic acid esters to the CH(2)OH function, displacing the CH(2)OH function with a dimethylaminocarboxamido group or with a methyl function introduced at the meta-, para- or ortho-position to the NH(2) group to form 5-(9-acridinylamino)-m-toluidines (AMTs), 5-(9-acridinylamino)-p-toluidines (APTs) or 5-(9-acridinylamino)-o-toluidines (AOTs), respectively. The inhibitions of a variety of human tumor cell growth, interactions with DNA as well as inhibitory effect against topoisomerase II (Topo II) of these new agents were studied. Among AMT, APT and AOT derivatives with dimethylaminoethylcarboxamido and Me at C4 and C5 of acridine moiety (i.e., 21c, 23c and 26c) were more cytotoxic than AHMA (1) and AHMA-ethylcarbamate (2), depending upon the tumor cell line tested. Detailed structure-activity relationships of the new analogues were studied.     

Design,synthesis and biological evaluation of novel 3-substituted 4-anilino-coumarin derivatives as antitumor agents

Various 3-substituted 4-anilino-coumarin derivatives have been designed, synthesized and their anti-proliferative properties have been studied. The in vitro cytotoxicity screening was performed against MCF-7, HepG2, HCT116 and Panc-1 cancer cell lines by MTT assay. Most of the synthesized compounds exhibited comparable anti-proliferative activity to the positive control 5-Fluorouracil against these four tested cancer cell lines. Among the different substituents at C-3 position of coumarin scaffold, 3-trifluoroacetyl group showed the most promising results. Especially, compounds 33d (IC₅₀ = 16.57, 5.45, 4.42 and 5.16 μM) and 33e (IC₅₀ = 20.14, 6.71, 4.62 and 5.62 μM) showed excellent anti-proliferative activities on MCF-7, HepG2, HCT116 and Panc-1 cell lines respectively. In addition, cell cycle analysis and apoptosis activation revealed that 33d induced G2/M phase arrest and apoptosis in MCF-7 cells in a dose-dependent manner. Low toxicity of compounds 33d and 33e was observed against human umbilical vein endothelial cells (HUVECs), suggesting their acceptable safety profiles in normal cells. Furthermore, the results of in silico ADME studies indicated that both 33d and 33e exhibited good pharmacokinetic properties.     

Synthesis and biological evaluation of baicalein derivatives as potent antitumor agents

Baicalein (5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one), a major flavonoid extracted from the root of Scutellaria baicalensis Georgi (Chinese name: Huangqin), showed potent anti-proliferative activity against a broad panel of human cancer cell lines both in vitro and in vivo. A novel series of baicalein derivatives were synthesized by introducing a group to C6-OH and a nitrogen-containing hydrophilic heterocyclic ring to C7-OH via a length of 3 or 4-carbon chain in this study. The in vitro antiproliferative activities of the 30 derivatives against HepG2, A549, BCG-823 cancer cell lines were evaluated. Among them, 10 compounds exhibit more potent cytotoxicity than baicalein against the three cancer cell lines. The most potent compound 9b possesses highest anti-proliferative potency against HepG2, A549, and BCG-823 with an IC₅₀ value of 2.0 μM, 0.8 μM and 3.2 μM, respectively. Preliminary mechanism studies with compound 9b using Annexin V/PI double-staining assay and DAPI staining assay indicated that 9b inhibits tumor cell proliferation potentially through inducing apoptosis.     

Design,synthesis and biological evaluation of novel thieno[3,2-d]pyrimidine and quinazoline derivatives as potent antitumor agents

Four series of novel thieno[3,2-d]pyrimidine and quinazoline derivatives containing N-acylhydrazone or semicarbazone were designed, synthesized, and evaluated for their biological activity. Of which compound 14 showed the most potent antitumor activities with IC₅₀ values of 1.78 μM, 1.02 μM, 1.98 μM, 0.41 μM and 0.22 μM against HT-29, MDA-MB-231, U87MG, PC-3 and HCT-116 cell lines respectively. Inhibition of enzymatic assays showed that PI3Kα was very likely to be one of the drug targets of 14 with the IC₅₀ value of 0.20 μM. According to the results of antitumor activity, the SARs were summarized, which indicated that thieno[3,2-d]pyrimidine and semicarbazone are optimal fragments. In addition, compounds with hydroxyl group at the 4-position on the terminal phenyl ring were more active. Annexin-V and propidium iodide (PI) double staining confirmed that the most active cytotoxic compound 14 can induce cell apoptosis in HCT-116 cells. Moreover, the influence of 14 on the cell cycle distribution was assessed on the HCT-116 cell line, exhibiting a cell cycle arrest at the G2/M phase. Furthermore, molecular docking analysis was also performed to determine possible binding modes between PI3Kα and the target compound. These results will guide us to further refine the structure of the thieno[3,2-d]pyrimidine and quinazoline derivatives to achieve optimal antitumor activity.     

Synthesis, biological evaluation and molecular docking studies of 1,3,4-thiadiazole derivatives containing 1,4-benzodioxan as potential antitumor agents

A series of 1,3,4-thiadiazole derivatives containing 1,4-benzodioxan (2a-2s) have been synthesized to screen for FAK inhibitory activity. Compound 2p showed the most potent biological activity against HEPG2 cancer cell line (EC(50)=10.28 μg/mL for HEPG2 and EC(50)=10.79 μM for FAK), which was comparable to the positive control. Docking simulation was performed to position compound 2p into the FAK structure active site to determine the probable binding model. The results of antiproliferative and Western-blot assay demonstrated that compound 2p possessed good antiproliferative activity against HEPG2 cancer cell line. Therefore, compound 2p with potent FAK inhibitory activity may be a potential anticancer agent against HEPG2 cancer cell.     

Synthesis and biological evaluation of NQO1-activated prodrugs of podophyllotoxin as antitumor agents

Podophyllotoxin (PPT), a toxic polyphenol derived from the roots of genus Podophyllum, had been reported with strong inhibition on both normal human cells and tumor cells, which hindered the development of PPT as the candidate antitumor agent. In the present work, multiple NQO1-activatable PPT prodrugs were synthesized for reducing normal cell toxicity and keeping tumor cell toxicity. The antiproliferative activities in vitro showed prodrug 3 was greatly selectively toxic to tumor cells over-expressing NQO1, taxol-resistant A549, hypoxia A549 and HepG2, and lower damage to normal cells in comparison with podophyllotoxin, prodrug 1 and 2. As elucidated by further mechanistic research, prodrug 3 was activated via NQO1 to efficiently while gently produce cytotoxic PPT units and kill tumor cells. In additions, in vivo study revealed that 3 significantly suppressed cancer growth in HepG2 xenograft models without obvious toxicity. Therefore, this NQO1-activatable prodrug delivery system exhibits good biosafety and provides a novel strategy for the development of drug delivery systems.     

Design,synthesis, and biological evaluation of biotinylated colchicine derivatives as potential antitumor agents

Chemical drug design based on the biochemical characteristics of cancer cells has become an important strategy for discovering new anti-tumour drugs to improve tumour targeting effects and reduce off-target toxicities. Colchicine is one of the most prominent and historically microtubule-targeting drugs, but its clinical applications are hindered by notorious adverse effects. In this study, we presented a novel tumour-specific conjugate 9 that consists of deacetylcolchicine (Deac), biotin, and a cleavable disulphide linker. 9 was found to exhibit potent anti-tumour activity and exerted higher selectivity between tumour and nontarget cells than Deac. The targeting moiety biotin might enhance the transport capability and selectivity of 9 to tumour cells via biotin receptor-mediated endocytosis. The tubulin polymerisation activity of 9 (with DTT) was close to the parent drug Deac. These preliminary results suggested that 9 is a high potency and reduced toxicity antitumor agent and worthy of further investigation.     

Synthesis and biological evaluation of disubstituted amidoxanthones as potential telomeric G-quadruplex DNA-binding and apoptosis-inducing agents

A series of disubstituted xanthones was obtained by cationic modification of xanthone’s C2 and C7 with amine groups of different pKa values. Modified structures by using moieties with high pKa values had good antitumor activity according to the MTT assay, AO/EB staining and flow cytometry assay, especially bis-dimethylamine derivative (5a). Further study indicated that compound 5a had good binding activity to telomeric G-quadruplex DNA, as detected by using spectroscopy methods, melting profiles, polymerase chain reaction stop assay and molecular modeling study. The results suggested that the antitumor activity of 5a might be associated with its stabilization of G-quadruplex DNA, which could be developed as new G-quadruplex DNA stabilizer and potent antitumor agents.     

Antitumor agents 273. Design and synthesis of N-alkyl-thiocolchicinoids as potential antitumor agents

As a part of our continuing study of colchicinoids as therapeutically useful antitumor drugs, thiocolchicine derivatives, including their phosphate and other water soluble salts, were synthesized and evaluated for inhibition of tubulin polymerization and for in vitro cytotoxicity. Three compounds, 7, 10, and 11, showed potent inhibition of tubulin assembly (IC₅₀ = 0.88–1.1 μM). In addition, compound 7, a water soluble succinic acid salt of N-deacetylthiocolchicine (4), showed potent cytotoxicity against a panel of tumor cell lines, suggesting it might be a potential lead to be developed as a therapeutic antitumor agent. Compound 8, a water soluble succinic acid salt of N,N-dimethyl-N-deacetylthiocolchicine (5), showed selective activities against HCT-8 and SK-BR-3 cells. N,N-Diethyl-N-deacetylthiocolchicine (6) seemed not to be a substrate for the P-gp efflux pump, based on the similar ED₅₀ values obtained against P-gp over-expressing KBvin (0.0146 μg/mL) cells and the parent KB (0.0200 μg/mL) cell line.     

First synthesis of 12-oxosoladulcidine and its derivatives as potential antitumor steroidal alkaloids

The first synthesis of 12-oxosoladulcidine (= (3beta,5alpha,22alpha,25R)-3-hydroxyspirosolan-12-one; 4) is reported, and its structure was confirmed by single-crystal X-ray diffraction analysis. Compound 4 was readily obtained in five steps in an overall yield of 31%, starting from hecogenin (5). By slightly modifying the synthetic protocol, eight analogues of 4 were also prepared. The title compound and its derivatives are expected to be potent antitumor alkaloids, since structurally closely related to the known antitumor agents soladulcidine (2) and hecogenin (5).     

Design,synthesis and biological activities of sorafenib derivatives as antitumor agents

A series of novel sorafenib derivatives, 9a–w, was designed and synthesized in high yields using various substituted anilines, and their antiproliferative activities against HCT116, PC-3 and MDA-MB-231 cell lines were also evaluated and described. All compounds exhibited potent antiproliferative activity against HCT116 and PC-3 cells with IC₅₀ = 2.8–52.0 and 2.2–45.6 μM; compounds 9p and 9q demonstrated competitive antiproliferative activities to sorafenib against all three cancer cell lines, the cytotoxicity of compound 9r is more potent than that of sorafenib. Compounds (9g, 9p, 9q and 9r) were chosen for further evaluation of the anti-angiogenesis activity, and showed the inhibition of sprout formation from aortic ring ex vivo. The structures of all the newly synthesized compounds were determined by ¹H NMR, ¹³C NMR and HRMS.     

Synthesis and biological evaluation of novel exo-methylene cyclopentanone tetracyclic diterpenoids as antitumor agents

The structure of exo-methylene cyclopentanone, which exists in nature tetracyclic diterpenoids products, has been proved to be an innate group for the treatment of cancer and inflammation. In this letter, four different scaffolds of tetracyclic diterpenoids including the structure exo-methylene cyclopentanone were synthesized from steviol and isosteviol and evaluated in vitro for their antitumor activity against three human cancer lines. Compounds 1a, 1b, 2b and 3b showed significant cytotoxicity, particularly, tetracyclic diterpenoids 2b, 3b were identified as the most potent and selective anticancer agents superior to adriamycin with IC₅₀ values of 0.9 μM and 1.5 μM, against Hep-G2 and MDA-MB-231 cell lines, respectively.     

Design,synthesis and biological activities of Nilotinib derivates as antitumor agents

A novel class of Nilotinib derivatives, B1–B20, were synthesized in high yields using various substituted anilines. All the title compounds were evaluated for their inhibitory activities against Bcr–Abl and antiproliferative effects on human leukemia cell (K562). The pharmacological results indicated that some compounds exhibited promising anticancer activity. In particular, compound B14 containing tertiary amine side chain exhibited Bcr–Abl inhibitory activity similar to that of Nilotinib. It was suggested that the introduction of the tertiary amine moiety could improve Bcr–Abl inhibitory activity and antitumor effects.     

Novel thiosemicarbazone derivatives as potential antitumor agents: Synthesis, physicochemical and structural properties, DNA interactions and antiproliferative activity

The paper describes synthesis of several novel thiosemicarbazone derivatives. Furthermore, crystal and molecular structure of 4-diethylamino-salicylaldehyde 4-phenylthiosemicarbazone revealed planarity of conjugated aromatic system, which suggested the possibility of DNA binding by intercalation, especially for here studied naphthalene derivatives. However, here presented DNA binding studies excluded this mode of action. Physicochemical and structural properties of novel derivatives were compared with previously studied analogues, taken as reference compounds, revealing distinctive differences. In addition, novel thiosemicarbazone derivatives (1, 2 and 5–8) clearly display stronger antiproliferative activity on five tumor cell lines than the reference compounds 3 and 4, which supports their further investigation as potential antitumor agents.     

Design,synthesis and biological evaluation of novel antitumor spirodihydrothiopyran-oxindole derivatives

Sulfur containing spiroheterocyclic oxindoles are promising privileged scaffolds in medicinal chemistry and drug discovery. Previously, we identified a new class of spirodihydrothiopyran-oxindoles with good in vitro antitumor activity against A549 lung cancer cell line. Herein, various spirooxindole-dihydrothiopyrans with diverse substitutions were synthesized and assayed to investigate the structure-activity relationships. Among the derivatives, compounds 4b, 4i, 4m, 4n and 4q displayed superior or comparable antitumor activity than nutlin-3. Molecular mechanism study revealed this scaffold displayed moderate MDM2 inhibitory activity, significantly induced cancer cell apoptosis and arrested cell cycle at G0/G1 phase, which represented a good lead compound for antitumor drug discovery.     

Efficient synthesis of Hsp90 inhibitor dimers as potential antitumor agents

The PU-H58-dimers 13a–15b were efficiently synthesized and their biological properties were evaluated. The copper-catalyzed alkyne azide coupling was effective in simultaneously linking three components via a triazole formation to afford the target dimers. These synthesized dimers exhibited binding affinity to the N-terminal domain of Hsp90, cytotoxicity, and client degradation activity although these activities were comparative or weak comparable with that of the parent compound.