Design,synthesis and structure–activity relationships of mangostin analogs as cytotoxic agents

In order to better understand the structure–activity relationship of mangostin, a series of xanthone derivatives based on α-mangostin were designed and synthesized. All the compounds were evaluated for their cytotoxicity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7 and SW480) using MTT assays. Most of them showed cytotoxicity and most of all, compounds 1a and 2h showed the highest cytotoxic potency by HL-60 cancer cell lines with IC₅₀ values of 5.96 μM and 6.90 μM respectively; compound 3e showed the highest cytotoxic potency against SMMC-7221 cancer cell line with IC₅₀ values of 3.98 μM; compounds 2e and 2m showed lower cytotoxicity but higher selectivity than α-mangostin against HL-60 and SMMC-7221 cancer cell lines respectively. Structure–activity relationship analysis indicates that the maintenance of the isopentene group at C-8 is essential for the cytotoxic activity.

A series xanthone derivatives were synthesized and cytotoxicity results indicated that the isopentene group at C-8 is essential.     

Substituted spirooxindole derivatives as potent anticancer agents through inhibition of phosphodiesterase 1

Spirooxindole is a promising chemo therapeutic agent. Possible targets include cancers of the liver, prostate, lung, stomach, colon, and breast. Here, we demonstrate a one-pot three-component reaction via a [3 + 2] cycloaddition/ring contraction sequence of a dipolarophile (activated alkene) with in situ-generated azomethine ylide (1,3-dipoles) without the use of any catalyst. The reaction provides efficient access to synthetically useful and biologically important spirooxindoles in high yield (69–94%) with high diastereoselectivity. The synthesized compounds were subjected to cytotoxicity evaluation using colorectal cancer (HCT-116), hepatocellular carcinoma (HepG2), and prostate cancer (PC-3) cells. Compounds 4i, 4j, and 4k showed potent cytotoxic activity and high selectivity against HCT-116 cells when compared to cisplatin. Meanwhile compound 4d retained high cytotoxic activity and selectivity against HepG2 and PC-3 cells in comparison to cisplatin. The mechanism of compound 4d was further studied using phosphodiesterase 1 enzyme and showed 74.2% inhibitory activity. A possible binding mode for compound 4d to PDE-1 was investigated by molecular modeling using OpenEye software. Pose predictions for the active compounds were demonstrated by ROCS alignments. Compound 4d has a special geometry and differs from other active compounds.

Spirooxindole is a promising chemo therapeutic agent. Possible targets include cancers of the liver, prostate, lung, stomach, colon, and breast.     

Two decades of advances in diterpenoid alkaloids with cytotoxicity activities

The important pharmacological activities and structural complexity of diterpenoid alkaloids have long stimulated strong scientific interest; some of these naturally abundant compounds have been reported to be highly promising for treating cancer. From 2008 to 2018, the cytotoxicity activities of more than 250 diterpenoid alkaloids were tested against several cancer cell lines. This review focuses on the progress of diterpenoid alkaloids with different structures derived from Ranunculaceae plants and some of their derivatives with potential anticancer activities. Then, we discuss the application prospects and development of active diterpenoid alkaloids.

The important pharmacological activities and structural complexity of diterpenoid alkaloids have long stimulated strong scientific interest; some of these naturally abundant compounds have been reported to be highly promising for treating cancer.     

Coumarin–carbazole based functionalized pyrazolines: synthesis,characterization, anticancer investigation and molecular docking

A series of novel pyrazoline scaffolds from coumarin–carbazole chalcones were synthesized. We explored various acetyl, amide, and phenyl substituents at the N-1 position of the pyrazoline core. The synthesized compounds were characterized by FTIR, ¹H-NMR, ¹³C-NMR, DEPT, and mass spectroscopic techniques. The in vitro cytotoxicity study of all the synthesized compounds was evaluated against HeLa, NCI-H520 and NRK-52E cell lines. Compounds 4a and 7b became the most active compounds and exhibited their potential to arrest the cell cycle progression and induce apoptosis in both the cell lines. In addition, molecular docking studies revealed a higher binding affinity of both the molecules with CDK2 protein. Based on the obtained results, a comprehensive analysis is warranted to establish the role of compounds 4a and 7b as promising cancer therapeutic agents.

Coumarin–carbazole based functionalised pyrazolines: synthesis, anticancer activity and molecular docking.     

Carotane sesquiterpenoids A–G from the desert endophytic fungus Fusarium sp. HM 166

Seven undescribed carotane sesquiterpenoids named fusanoids A–G (1–7), along with one known analog (8) and two known sesterterpenes (9 and 10), were isolated from the fermentation broth of the desert endophytic fungi Fusarium sp. HM166. The structures of the compounds, including their absolute configurations, were determined by spectroscopic data, single-crystal X-ray diffraction analysis, and ECD calculations. Compound 10 showed cytotoxic activities against human hepatoma carcinoma cell line (Huh-7) and human breast cell lines (MCF-7 and MDA-MB-231), and compound 2 showed cytotoxic activity against MCF-7, while compounds 4–9 were inactive against all the tested cell lines. Compounds 4 and 10 showed potent inhibitory activities against the IDH1^R132h mutant.

Seven undescribed carotane sesquiterpenoids were isolated from the endophytic fungi Fusarium sp. HM166. Single-crystal X-ray diffraction and ECD defined absolute configurations. Cytotoxicity for Huh-7, MCF-7, and MDA-MB-231 cancer cell lines and IDH1^R132h mutant were studied.     

Pyrazole-based lamellarin O analogues: synthesis,biological evaluation and structure–activity relationships

A library of pyrazole-based lamellarin O analogues was synthesized from easily accessible 3(5)-aryl-1H-pyrazole-5(3)-carboxylates which were subsequently modified by bromination, N-alkylation and Pd-catalysed Suzuki cross-coupling reactions. Synthesized ethyl and methyl 3,4-diaryl-1-(2-aryl-2-oxoethyl)-1H-pyrazole-5-carboxylates were evaluated for their physicochemical property profiles and in vitro cytotoxicity against three human colorectal cancer cell lines HCT116, HT29, and SW480. The most active compounds inhibited cell proliferation in a low micromolar range. Selected ethyl 3,4-diaryl-1-(2-aryl-2-oxoethyl)-1H-pyrazole-5-carboxylates were further investigated for their mode of action. Results of combined viability staining via Calcein AM/Hoechst/PI and fluorescence-activated cell sorting data indicated that cell death was triggered in a non-necrotic manner mediated by mainly G2/M-phase arrest.

Isosteric pyrrole–pyrazole exchange in the natural alkaloid lamellarin O resulted in 18 fully characterized derivatives. Obtained compounds were investigated as potent agents against human colon cancer cell lines HCT116, HT29 and SW480.     

New spirobisnaphthalenes from an endolichenic fungus strain CGMCC 3.15192 and their anticancer effects through the P53–P21 pathway

Natural products from fungi have remained a rich resource for drug discovery. Here we report the isolation of three new spirobisnaphthalenes, namely sacrosomycin A-C (1–3), and three known analogues (4–6), from the ethyl acetate extract of a nonsporulating endolichenic fungus derived from Peltigera elisabethae var. mauritzii. The structures of these compounds were elucidated by IR, UV, MS, and NMR. Biological functions of these compounds were evaluated using cultured human cancer cell lines. Short-term cell growth and long-term cell survival assays show that compound 5 demonstrated the strongest cancer cell growth inhibition effect. We reveal that compound 5 induced both cell cycle arrest at the G2/M phase and cell death. Using western blotting, luciferase reporter assay and quantitative PCR (qPCR), we show that compound 5 induced up-regulation of the P53–P21 pathway, supporting the cell cycle arrest and growth inhibition effect of this compound. In contrast, these compounds did not induce cell death in a normal cell line. These results demonstrate a potential anticancer effect of this rare family of spirobisnaphthalene compounds isolated from endolichenic fungi.

New spirobisnaphthalenes from an endolichenic fungus strain and their anticancer effects mediated by the P53–P21 pathway.     

First synthesis of novel 2,4-bis((E)-styryl)quinoline-3-carboxylate derivatives and their antitumor activity

A simple and flexible synthesis of a new series of 2,4-bis((E)-styryl)quinoline-3-carboxylates (3a–t) has been achieved for the first time in good yields via successive Arbuzov/Horner–Wadsworth–Emmons (HWE) reaction in one-pot using the newly-synthesized ethyl 4-(bromomethyl)-2-(chloromethyl)quinoline-3-carboxylate as the substrate. Our synthetic protocol is as attractive and powerful as it is simple, tolerates a wide range of substituents, and does not involve the use of expensive reagents or catalysts. These title compounds belong to a new class of quinoline derivatives and their antitumor activity was assessed on human cancer cell lines (A549, HT29 and T24). The MTT assay showed compounds 3h, 3k and 3t had significant inhibitory activity with IC₅₀ values of 1.53, 1.38 and 2.36 μM against A549 and 1.50, 0.77 and 0.97 μM against HT29, respectively, much better than the reference cisplatin.

One-pot successive Arbuzov/HWE synthesis and preliminary antitumor activity evaluation of 2,4-di((E)-styryl)quinoline-3-carboxylates was described in this study.     

Berberine-based carbon dots for selective and safe cancer theranostics

Fluorescent berberine-based carbon dots (Ber–CDs) were prepared through a facile synthesis strategy. Ber–CDs exhibited excellent optical properties for bioimaging and retained the biofunctions of berberine, and enabled selective and safe anti-tumor performance, demonstrating their promising application potential in cancer theranostics.

Fluorescent berberine-based carbon dots (Ber–CDs) were prepared through a facile synthesis strategy.     

Synthesis and biological study of acridine-based imidazolium salts

A new series of acridine based imidazolium salts was synthesized and evaluated for in vitro cytotoxicity against human cancer cell lines by an MTT assay. The synthesis applied a coupling of imidazoles with 9-chloroacridines, which originated from an Ullmann condensation of a 2-chloro-benzoic acid with an aniline. The target compounds were obtained in high yields. The DPPH assay indicated considerable antioxidant activity for target compounds with simple and short alkyl chains on the imidazole, while increasing chain length and the introduction of an additional π-electron system in most cases reduced the activity. All compounds exhibited low biotoxicity against non-cancerous cell lines, whereas a few compounds showed promising anticancer activity. Unlike for the reference drugs Tamoxifen and Paclitaxel, the anticancer activity of acridine imidazolium ions is specific for only selected cancer types. Reasonable fluorescent behaviour of the products provide potential for visualization of the distribution of active drugs in tissue.

A series of acridine-based imidazolium salts was synthesized and studied on cytotoxicity against human cancer cell lines.     

Synthesis and insight into the structure–activity relationships of 2-phenylbenzimidazoles as prospective anticancer agents

In order to explore and develop new anticancer agents, three series of 2-phenylbenzimidazoles, 15–46, were condensed under simple and mild conditions using sodium metabisulfite as an oxidation agent and another series, 47–55, were obtained via a reduction reaction using sodium borohydride. All the compounds synthesized were evaluated for their in vitro anticancer activities against three human cancer cell lines. The novel compound 38 was found to be the most potent multi cancer inhibitor against A549, MDA-MB-231, and PC3 cell lines (IC₅₀ values 4.47, 4.68 and 5.50 μg mL⁻¹, respectively). In addition, compound 40 exhibited the best IC₅₀ value of 3.55 μg mL⁻¹ against the MDA-MB-231 cell line. The results demonstrated that introducing a new substituent to compounds 37–55 could improve their antiproliferative activities.

Three series of 2-phenylbenzimidazoles obtained under simple and convenient pathways, were used to elucidate their SARs against three cancer cell lines: A549, MDA-MB-231 and PC3.     

Schweinfurthins A–Q: isolation,synthesis, and biochemical properties

Stilbene analogues have shown remarkable structural diversity constituting simple or tangled structures, which have attracted the synthetic as well as the medicinal chemistry communities. Schweinfurthins are a family of prenylated/geranylated/farnesylated stilbenes that are isolated from an African plant belonging to the Macaranga species. These compounds have displayed potency towards central nervous system, renal and breast cancer cell lines. Specifically, these compounds have been found to be potent and selective inhibitors of cell growth in the National Cancer Institute''s 60 cell-line screen. In this review article, we described the isolation, synthesis, and biochemical properties of schweinfurthins.

An overview of the isolation, synthesis, and biochemical properties of the stilbene-based natural products schweinfurthins A–Q (1999–2017).     

Synthesis and biological evaluation of dehydroabietic acid-pyrimidine hybrids as antitumor agents

A series of novel dehydroabietic acid derivatives containing pyrimidine moieties were designed and synthesized to explore more efficacious and less toxic antitumor agents according to the principle of combination and hybridization. The cytotoxicity against human liver cancer (HepG2) cells, human breast cancer (MCF-7) cells, human colon cancer (HCT-116) cells, human lung cancer (A549) cells, and human normal liver cells (LO2) was estimated by MTT assay in vitro. Cytotoxic activity screening revealed that most of the compounds showed moderate to high levels of cytotoxicity against these four cancer cell lines and that some displayed more potent inhibitory activities compared with 5-FU. In particular, compound 3b exhibited promising cytotoxicity with IC₅₀ values ranging from 7.00 to 11.93 μM against all the tested cell lines and displayed weak cytotoxicity towards normal cells. Besides, cell cycle analysis indicated that compound 3b mainly arrested MCF-7 cells at the S stage and induced cell apoptosis.

A series of novel dehydroabietic acid derivatives containing pyrimidine moieties were designed and synthesized. Some of them displayed more potent inhibitory activities compared with 5-FU.     

Melodinines Y1–Y4, four monoterpene indole alkaloids from Melodinus henryi

Melodinines Y₁–Y₄ (1–4), four undescribed alkaloids were isolated from Melodinus henryi. Their structures were elucidated by extensive NMR, mass spectroscopic analyses, theoretical NMR and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 are the first examples of bisindole alkaloids possessing an eburnamine–leuconoxine combination. Compound 3 is a rare 2,3-seco pleiocarpamine type monoterpene indole alkaloid. Compound 1 showed cytotoxic activities against six human cancer cell lines with IC₅₀ values of 0.5–15.2 μM.

Monoterpenoid indole alkaloids from Melodinus henryi     

Anticancer activity of pyrimidodiazepines based on 2-chloro-4-anilinoquinazoline: synthesis,DNA binding and molecular docking

Multidrug resistance to chemotherapy is a critical health problem associated with mutation of the therapeutic target. Therefore, the development of anticancer agents remains a challenge to overcome cancer cell resistance. Herein, a new series of quinazoline-based pyrimidodiazepines 16a–g were synthesized by the cyclocondensation reaction of 2-chloro-4-anilinoquinazoline-chalcones 14a–g with 2,4,5,6-tetraaminopyrimidine. All quinazoline derivatives 14a–g and 16a–g were selected by the U.S. National Cancer Institute (NCI) for testing their anticancer activity against 60 cancer cell lines of different panels of human tumors. Among the tested compounds, quinazoline-chalcone 14g displayed high antiproliferative activity with GI₅₀ values between 0.622–1.81 μM against K-562 (leukemia), RPMI-8226 (leukemia), HCT-116 (colon cancer) LOX IMVI (melanoma), and MCF7 (breast cancer) cancer cell lines. Additionally, the pyrimidodiazepines 16a and 16c exhibited high cytostatic (TGI) and cytotoxic activity (LC₅₀), where 16c showed high cytotoxic activity, which was 10.0-fold higher than the standard anticancer agent adriamycin/doxorubicin against ten cancer cell lines. COMPARE analysis revealed that 16c may possess a mechanism of action through DNA binding that is similar to that of CCNU (lomustine). DNA binding studies indicated that 14g and 16c interact with the calf thymus DNA by intercalation and groove binding, respectively. Compounds 14g, 16c and 16a displayed strong binding affinities to DNA, EGFR and VEGFR-2 receptors. None of the active compounds showed cytotoxicity against human red blood cells.

A new series of quinazoline-based chalcones and pyrimidodiazepines were tested against 60 human tumor cell lines.     

New bioactive cyclopeptide alkaloids with rare terminal unit from the root bark of Ziziphus cambodiana

Six new 14-membered ring cyclopeptide alkaloids, cambodines A–F (1–6), and two known compounds, frangufoline (7) and lotusanine B (8), were isolated from the root bark extract of Ziziphus cambodiana Pierre. Their structures and configurations were established based on 1D and 2D NMR, HRMS, ECD, and X-ray crystallographic data. Compounds 1 and 3 are rare 5(14)-type cyclopeptide alkaloids that possess an imidazolidin-4-one ring in the terminal unit. The cyclopeptides were tested for their in vitro antiplasmodial, antitubercular, and cytotoxic effects against three cancer cell lines. Compound 3 showed significant antiplasmodial activity against the malarial parasite Plasmodium falciparum, with an IC₅₀ value of 6.09 μM.

Six new 14-membered ring cyclopeptide alkaloids, cambodines A–F (1–6), and two known compounds, frangufoline (7) and lotusanine B (8), were isolated from the root bark extract of Ziziphus cambodiana Pierre.     

Diastereoselective synthesis of novel spiro indanone fused pyrano[3,2-c]chromene derivatives following hetero-Diels–Alder reaction and in vitro anticancer studies

The development of concise methods for the synthesis of small functionalised spirocyclic molecules is important in the search of new bioactive molecules. To contribute this, here we represent a diastereoselective oxa-hetero-Diels–Alder reaction for the synthesis of novel spiro indanone fused pyrano[3,2-c]chromene derivatives and studied their in vitro anticancer activities. Using previously less explored cyclic ketone i.e. indane-1,3-dione and 3-vinyl-2H-chromene derivatives, we obtained novel spiro-heterocyclic frameworks at the interphase between “drug-like” molecules and natural products. Various spiro indanone fused pyrano[3,2-c]chromene derivatives were synthesized regiospecifically bearing a quaternary stereocenter in high yields (up to 85%) with excellent diastereoselectivity in toluene using 4 Å MS as additive under reflux condition at 120 °C. In vitro cytotoxic studies of these compounds against MCF-7 (breast cancer), HCT-116 (colon cancer), H-357 (oral cancer), MD-MB-231(Breast cancer) cell lines were evaluated by MTT {3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide} assay in vitro. The screening results revealed that many of the compounds are showing moderate to high levels of anticancer activities against the tested cancer cell lines and some displayed potent inhibitory activities in comparison to the commercial anticancer drug 5-fluorouracil (5-FU). Among the series, compound 3′c showed most potent cytotoxicity (15.0–27.5 μM) in three cancer cell lines (MCF-7, HCT-116 and MD-MB-231).

Synthesis of novel spiro indanone fused pyrano[3,2-c]chromene derivatives following hetero-Diels–Alder reaction has been demonstrated and evaluated for their in vitro anticancer activity.     

Transient directing group enabled Pd-catalyzed C–H oxygenation of benzaldehydes and benzylic amines

We report a general protocol for <i>ortho</i>-C–H fluoroalkoxylation of benzaldehydes and benzylic amines utilizing an inexpensive amino amide as a transient directing group. In the presence of an electrophilic fluorinating bystanding oxidant and fluorinated alcohols, a wide range of benzaldehydes and benzylic amines could be oxygenated selectively at the ortho positions to afford fluoroalkyl aryl ethers. This elegant approach would provide appealing strategies for synthesis of drug molecules and natural products.

A general protocol for ortho-C–H fluoroalkoxylation of benzaldehydes and benzylic amines was exploited by utilizing an inexpensive amino amide as a transient directing group.     

Cytotoxic polyhydroxylated pregnane glycosides from Cissampelos pareira var. hirsuta

Fourteen new polyhydroxylated pregnane glycosides, cissasteroid A–N (1–14), and five known analogues (15–19), were isolated from the dried whole plant of Cissampelos pareira var. hirsuta. Their structures and stereochemistry were elucidated by extensive spectroscopic data, chemical hydrolysis, and ECD measurements. All the compounds were tested for their cytotoxicity against five human cancer cell lines, and inhibitory activity against NO release in LPS-induced RAW 264.7 cells. Compared with cisplatin, compound 7 showed more potent cytotoxicities against the HL-60, A549, SMMC-7721, MCF-7, and SW480 cell lines, with IC₅₀ values of 2.19, 14.38, 2.00, 7.58, and 7.44 μM, respectively. The preliminary study of structure–activity relationship indicated that benzoic acid esterification at C-20 may have a negative effect on the cytotoxic activity of polyhydroxylated pregnane derivatives in these five human cancer cell lines. These results revealed the potential of compound 7 as an ideal antitumor lead compound.

Fourteen new polyhydroxylated pregnane glycosides, cissasteroid A–N (1–14), and five known analogues (15–19), were isolated from the dried whole plant of Cissampelos pareira var. hirsuta.     

Adamantyl and homoadamantyl derivatives from Garcinia multiflora fruits

Nine undescribed caged polycyclic polyprenylated acylphloroglucinols (PPAPs), including adamantane type PPAPs (1–2), and homoadamantane type PPAPs (3–9), were isolated from the fruits of Garcinia multiflora, along with three known analogues. A new epimeric pair of isohypersampsonone B (5) and epi-isohypersampsonone B (6), featuring an unusual hexahydrofuro[2,3-b]furan-diepoxy ring system fused in a homoadamantane skeleton, was not separated due to the rapid equilibration between the two isomeric forms. All new caged PPAPs (1–9), sharing a common isogeranyl group, were determined on the basis of comprehensive NMR and MS spectroscopic data. Their cytotoxicity against three human tumor cell lines (SGC-7901, HepG2, HCT-116) and the nitric oxide production inhibitory activity of lipopolysaccharides-stimulated RAW 264.7 cells were tested. Compounds 8 and 12 displayed mild cytotoxicity against three human cancer cell lines with IC₅₀ values of 10–20 μM. Furthermore, compounds 8 and 12 also exhibited NO production inhibitory effect with an IC₅₀ value of 18.24 and 12.50 μM respectively.

Nine undescribed caged polycyclic polyprenylated acylphloroglucinols (PPAPs), including adamantane type PPAPs (1–2) and homoadamantane type PPAPs (3–9), were isolated from the fruits of Garcinia multiflora.