Human Solid Tumor Cell Lines Research Articles

Synthesis, anionophoric activity and apoptosis-inducing bioactivity of benzimidazolyl-based transmembrane anion transporters

In this paper we show that a series of 1,3-bis(benzimidazol-2-yl)benzene (m-Bimbe) derivatives exhibit excellent performance as transmembrane anion transporters with anticancer activity. The transport efficiency of m-Bimbe and its derivatives has been firstly optimized by adding a strong electron-withdrawing nitro group at the 5-position of the central phenyl subunits to enhance the CH···anion interactions. Evidences for the interactions were obtained from ESI MS, spectrophotometric and 1H NMR titrations. These compounds exhibit potent anionophoric activity in both liposomal models and live cells. In particular, the 5-nitrated derivatives having nitro or trifluoromethyl groups at the benzimidazoloyl subunits exhibit 2370- and 1721-fold enhanced anionophoric activity with the EC50 values as low as 36 and 50 nM, respectively. These compounds can disturb the cellular homeostasis of chloride anions, modify the intracellular pH and induce the basification of acidic organelles. Most of this series of m-Bimbe derivatives exhibit potent cytotoxicity toward the tested human solid tumor cell lines, and the 5-nitrated derivative bearing trifluoromethyl groups at the benzimidazoloyl subunits is the most active with the IC50 value in the low micromolar range. Mechanistic studies suggest that the transport of chloride anions across the cellular membranes plays a critical role in the cytotoxic effect and these compounds induce cell death probably via an apoptotic process.

Magnetic field direction differentially impacts the growth of different cell types

ABSTRACTMagnetic resonance imaging (MRI) machines have horizontal or upright static magnetic field (SMF) of 0.1–3 T (Tesla) at sites of patients and operators, but the biological effects of these SMFs still remain elusive. We examined 12 different cell lines, including 5 human solid tumor cell lines, 2 human leukemia cell lines and 4 human non-cancer cell lines, as well as the Chinese hamster ovary cell line. Permanent magnets were used to provide 0.2–1 T SMFs with different magnetic field directions. We found that an upward magnetic field of 0.2–1 T could effectively reduce the cell numbers of all human solid tumor cell lines we tested, but a downward magnetic field mostly had no statistically significant effect. However, the leukemia cells in suspension, which do not have shape-induced anisotropy, were inhibited by both upward and downward magnetic fields. In contrast, the cell numbers of most non-cancer cells were not affected by magnetic fields of all directions. Moreover, the upward magnetic field inhibited GIST-T1 tumor growth in nude mice by 19.3% (p < 0.05) while the downward magnetic field did not produce significant effect. In conclusion, although still lack of mechanistical insights, our results show that different magnetic field directions produce divergent effects on cancer cell numbers as well as tumor growth in mice. This not only verified the safety of SMF exposure related to current MRI machines but also revealed the possible antitumor potential of magnetic field with an upward direction.

Two New Anti-Proliferative C18 -Norditerpenes from the Roots of Podocarpus macrophyllus.

Activity-guided fractionation strategy was used to investigate chemical constituents from the roots of Podocarpus macrophyllus. Successfully, two new norditerpenes, 2β-hydroxymakilactone A (1) and 3β-hydroxymakilactone A (2), along with ten known analogues (3-12) were isolated. The structures of 1 and 2 were elucidated by spectroscopic analysis including 1D-, 2D-NMR, and HR-ESI-MS data. The previously reported structure of 2,3-dihydro-2α-hydroxypodolide was revised as 2,3-dihydro-2β-hydroxypodolide (3) by spectroscopic analysis, and was further confirmed by X-ray crystallographic analysis. Cytotoxic activities of all isolated compounds against five human solid tumour cell lines (AGS, HeLa, MDA-MB-231, HepG-2, and PANC-1) were evaluated. All of them exhibited anti-proliferative activities (IC50 =0.3-27μm), except for 10. Compounds 1, 4, 5, 6, and 8 exhibited potent inhibitory activities with IC50 <1μm against HeLa and AGS cells.

New Hybrids Derived from Podophyllic Aldehyde and Diterpenylhydroquinones with Selectivity toward Osteosarcoma Cells

A new family of molecular hybrids, between cyclolignans related to podophyllic aldehyde and several diterpenylnaphthohydroquinones (DNHQ), was prepared and its biological activity evaluated in several human solid tumor cell lines, which are representative of the most prevalent solid tumors in the Western world. Both cyclolignan and quinone fragments were linked through aliphatic or aromatic spacers. The new hybrid family was evaluated for its cytotoxicity, and it was found that the hybrids were several times more potent against the osteosarcoma cell line MG-63 than against MCF-7 and HT-29 cell lines. The presence of an aromatic ring in the linker gave the most potent and selective agent, improving the cytotoxicity of the parent compounds. Cell cycle studies demonstrated that this hybrid induces a strong and rapid apoptotic effect and arrests cells at the G2/M phase of the cell cycle, in the same way that the parent compound podophyllic aldehyde does.

Abstract P1-10-15: Development of humanized anti-CD47 monoclonal antibodies with differentiated functional profiles

Abstract CD47 is a cell surface transmembrane protein that binds to signal regulatory protein alpha (SIRPα) on macrophages and results in a “don't eat me” signal that inhibits phagocytosis. Breast cancer cells, both primary and metastatic, frequently overexpress CD47 and exploit this pathway to evade macrophage-mediated destruction. Anti-CD47 monoclonal antibodies (mAbs) block the CD47/SIRPα interaction and promote tumor cell destruction via phagocytosis. Anti-CD47 mAbs also contribute to an anti-tumor T-cell response in immune-competent mice. Therefore, anti-CD47 antibodies represent a new class of immune checkpoint inhibitors that modulate both the innate and adaptive immune systems. CD47 is expressed on multiple cell types, including tumor cells and normal cells. Many anti-CD47 mAbs block the CD47/SIRPα interaction and cause phagocytosis of tumor cells, but do not directly induce the death of human tumor cells. Tioma has created new humanized anti-CD47 mAbs with novel and differentiated functional profiles to enhance functional heterogeneity. Ti-104, Ti-176 and Ti-108 block the binding of SIRPα to CD47 and increase phagocytosis of human tumor cells. They also induce cell death of human hematological and solid tumor cell lines (including breast cancer lines) in a cell autonomous manner. Cell death was determined by an increase in phosphatidylserine-positive/7AAD-positive tumor cells assessed by flow cytometry following incubation in media containing anti-CD47 mAb or a negative control immunoglobulin. In vitro, these mAbs bind to human tumor cell lines with apparent binding affinities ranging from low pM to low nM, depending on the cell line and method of analysis (solid-phase or cell-based ELISA, flow cytometry or surface plasmon resonance). In vitro, Ti-104 and Ti-108 bind to human RBCs, whereas Ti-176 has markedly reduced binding to human and cynomolgus monkey RBCs. In a four-week (once-weekly dosing) exploratory safety study in cynomolgus monkeys with Ti-176 and Ti-108, no dose-limiting toxicity or gross pathological or microscopic findings were identified after an initial dose of 5 mg/kg (Week 1) followed by doses of 50 mg/kg (Weeks 2, 3, and 4). Ti-176 treatment resulted in minimal decrease in red cell mass, hemoglobin and hematocrit, which corresponded in vitro to markedly reduced binding to cynomolgus monkey RBCs. Ti-108 caused transient reduction of RBC parameters comparable to some previously reported anti-CD47 mAbs. Ti-104, Ti-176 and Ti-108 showed potent, dose-dependent efficacy in multiple mouse tumor models, including in the MDA-MB-231 triple-negative breast cancer orthotopic model. These data provide the preclinical rationale for further evaluation of Ti-104, Ti-176 and Ti-108 as breast cancer treatments. Citation Format: Karr RW, Liu K, Hiebsch R, Capoccia B, Donio M, Crowley K, Puro R, Chanda S, Manning P. Development of humanized anti-CD47 monoclonal antibodies with differentiated functional profiles [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-15.

Abstract A111: The alkyl phosphocholine analog CLR1404 delays radiation-induced dsDNA damage repair in pediatric and adult solid tumors

Abstract Exposure of normal tissues to radiation is a major limitation in cancer radiotherapy, with significant consequences particularly in the pediatric setting. Increasing the selective anticancer effect of radiation on malignant cells utilizing cancer-targeted drugs could provide an option to lessen adverse radiation effects on healthy tissue. We investigated the radiosensitizing properties of 18-(p-iodophenyl) octadecyl phosphocholine (CLR1404), a clinical-grade phospholipid ether analog with selective sequestration in cancer cells, in pediatric and adult human solid tumor cell lines. Preliminary data in our laboratory using a fluorescently-labeled analog indicated that human cancer cells uptake and retain 6- to 10-fold more CLR1404 when compared with normal primary cells. In vitro, the clonogenic survival of tumor cells after irradiation was significantly decreased when cells were pretreated with CLR1404. This radiosensitizing effect was detected also in vivo, in xenograft-bearing mice treated with CLR1404 during fractionated radiation, resulting in decreased tumor volumes and markedly delayed tumor regrowth in CLR1404-treated mice compared to controls. We investigated mechanisms responsible for the radiosensitizing properties of CLR1404. Western blotting of tumor cell lysates indicated increased accumulation and prolonged persistence of γ-H2AX in irradiated tumor cells pretreated with CLR1404 compared to nontreated controls. Expression of select markers of homologous and non-homologous end-joining dsDNA radiation damage repair pathways were markedly decreased and significantly delayed in CLR1404-treated tumor cells after exposure to irradiation compared to non-CLR1404-treated cells. CLR1404 treatment also markedly decreased the activation of p53 after irradiation in p53-functional rhabdomyosarcoma cells compared to cells treated with radiation alone. In conclusion, our data show that, in both pediatric and adult human solid tumor cell lines, the alkyl phosphocholine analog CLR1404 interferes with sensing of dsDNA damage, delays DNA damage repair, and potentially interferes with other cell survival mechanisms, for example involving p53. These mechanisms might be responsible for the observed in vitro and in vivo radiosensitizing properties of CLR1404. Tumor-targeted radiosensitization with CLR1404 could improve the selective antitumor effect of radiation, and provide a distinct therapeutic benefit to cancer patients. Citation Format: Ankita Shahi, Mohamed Y. Elsaid, Dana C. Baiu, Eric A. Armstrong, Jamey P. Weichert, Paul M. Harari, Mario Otto. The alkyl phosphocholine analog CLR1404 delays radiation-induced dsDNA damage repair in pediatric and adult solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A111.

Pinnatifidenyne-Derived Ethynyl Oxirane Acetogenins from Laurencia viridis.

Red algae of Laurencia continue to provide wide structural diversity and complexity of halogenated C15 acetogenin medium-ring ethers. Here, we described the isolation of three new C15 acetogenins (3–5), and one truncated derivative (6) from Laurencia viridis collected on the Canary Islands. These compounds are interesting variations on the pinnatifidenyne structure that included the first examples of ethynyl oxirane derivatives (3–4). The structures were elucidated by extensive study of NMR (Nuclear Magnetic Resonance) data, J-based configuration analysis and DFT (Density Functional Theory) calculations. Their antiproliferative activity against six human solid tumor cell lines was evaluated.

A green multicomponent synthesis of tocopherol analogues with antiproliferative activities

A one-pot efficient, practical and eco-friendly synthesis of tocopherol analogues has been developed using water or solvent free conditions via Passerini and Ugi multicomponent reactions. These reactions can be optimized using microwave irradiation or ultrasound as the energy source. Accordingly, a small library of 30 compounds was prepared for biological tests. The evaluation of the antiproliferative activity in the human solid tumor cell lines A549 (lung), HBL-100 (breast), HeLa (cervix), SW1573 (lung), T-47D (breast), and WiDr (colon) provided lead compounds with GI50 values between 1 and 5 μM. A structure–activity relationship is also discussed. One of the studied compounds comes up as a future candidate for the development of potent tocopherol-mimetic therapeutic agents for cancer.

Aethusifolins A–D: Four new components from a traditional Mongolian medicinal herb Clematis aethusifolia Turcz

Four new components named aethusifolins A–D (1–4), together with ten known (5–14) were isolated from the dried aerial parts of a traditional Mongolian medicinal herb Clematis aethusifolia Turcz. The planar structures were established based on extensive spectroscopic analysis (HRMS, 1D and 2D NMR), and the absolute configurations were determined by modified Mosher’s method, hydrolysis method. The cytotoxicities of isolated compounds against a panel of five human solid tumor cell lines were assayed. Compounds 5, 8, and 13 showed moderate cytotoxicity against A-375 with IC50 values of 15–18μM, while compound 8 also showed cytotoxicity against SH-SY5Y with IC50 values of 20μM.

Indium(III) complexes with 2-acetylpyridine-derived thiosemicarbazones exhibit cytotoxic activity against human leukemia and solid tumor cell lines

Complexes [In(2Ac4Ph)2]NO3·H2O (1), [In(2Ac4mClPh)2]NO3·1.5H2O (2), [In(2Ac4pClPh)2]NO3·2H2O (3) and [In(2Ac4pIPh)2]NO3·H2O (4) were obtained with N(4)-phenyl-2-acetylpyridine thiosemicarbazone (H2Ac4Ph), and its N(4)-meta-chlorophenyl-(H2Ac4mClPh), N(4)-para-chlorophenyl-(H2Ac4pClPh) and N(4)-para-iodophenyl-(H2Ac4pIPh) derivatives. The crystal structures of [In(2Ac4Ph)2]NO3·MeOH (1a), [In(2Ac4mClPh)2]NO3·EtOH·H2O (2a) and [In(2Ac4pClPh)2]·NO3 (3a) were determined. The cytotoxic effects of the thiosemicarbazone ligands and of complexes (1–4) were evaluated against HL-60, Jurkat and THP-1 leukemia cells and against MCF-7, MDA-MB-231 and HCT-116 solid tumor cells, as well as against mammalian healthy Vero cells. Upon coordination to indium(III) cytotoxicity increased in several cases. In addition, complex (1) was active in sub-micromolar doses against all tested cell lineages, with selectivity indexes (SI=IC50 Vero/IC50 tumor cell) ranging from 3 (against THP-1 cells) to 144 (against HCT-116 cells).

Abstract 5127: In vitro and in vivo evaluation of FF-10502-01, a new pyrimidine nucleoside analogue

Abstract Introduction:FF-10502-01 is a synthetic pyrimidine nucleoside analogue structurally similar to gemcitabine (gem) with a substitution of sulfur for oxygen in the pentose ring. The anti-tumor effects of FF-10502-01 were studied in solid tumor cell lines and human tumor xenograft models. Methods:10 human solid tumor cell lines were studied and included the following: 4 pancreatic (PANC) (BxPC-3, SUIT-2, Capan-1 and MIA PaCa-2), colon (HCT116), lung (NCI-H460), ovary (SK-OV-3), prostate (LNCap.FGC), breast (MDA-MB231) and mantle cell lymphoma (MCL) (Jeko-1). The effect of FF-10502-01 on DNA synthesis versus gem was evaluated in a PANC cell line (Capan-1). Tumor growth suppression was evaluated in human PANC xenograft models, SUIT-2 and Capan-1. FF-10502-01 or gem was administered at 240 or 480 mg/kg once a week starting 7d after orthotopic transplantation for 18 weeks, n=20/grp. Animals were followed for 128d after transplantation. Capan-1 was transplanted SC into nude mice (n=8/grp). FF-10502-01 or gem was administered at 120, 240, 360 or 480 mg/kg once weekly x 4 weeks 7d after transplantation. Tumor growth inhibitory effects were evaluated for 27d after starting treatment. FF-10502-01 single-dose pharmacokinetics (PK) were investigated in the mouse, rat and dog. Results:FF-10502-01 demonstrated in vitro activity against the PANC, colon, lung, ovarian, prostate and MCL cell lines, with IC50s of 30 – 330 nM. The activity was 1.5 – 15-fold lower than gem, however, FF-10502-01 demonstrated a 23-fold higher inhibition of DNA α-polymerase-mediated synthesis over gem. In the SUIT-2 orthotropic implant model, both gem and FF-10502-01 improved survival over vehicle controls. Med survival was not reached for the 480 mg/kg gem grp or either the 240 or 480 mg/kg FF-10502-01 grps. The survival rate was 5%, 25%, 75% for the vehicle, 240 and 480 mg/kg gem grps (p&amp;lt;0.0001 versus vehicle), and 100% for the 240 and 480 mg/kg FF-10502-01 grps (p&amp;lt;0.0001 versus gem grps), respectively. In the Capan-1 xenograft model, both FF-10502-01 and gem demonstrated statistically significant tumor growth suppression versus vehicle control; FF-10502-01 demonstrated equivalent tumor growth suppression with less effect on body weight than gem at clinically achievable doses. PK following single bolus IV doses indicated a similar PK profile to other pyrimidine nucleoside analogues, including gem. Conclusions:FF-10502-01 is a new pyrimidine nucleoside analogue with demonstrated preclinical efficacy against solid tumors and a potentially more tolerable safety profile than gem. Citation Format: Shinji Mima, Hiroki Nishikawa, Shinichi Watanabe, Tamami Higuchi, Takeaki Suzuki, Hiroyuki Iwamura, Chihaya Kakinuma, Takaaki Nakamura, Yasuhiro Shimada. In vitro and in vivo evaluation of FF-10502-01, a new pyrimidine nucleoside analogue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5127. doi:10.1158/1538-7445.AM2017-5127

Abstract DDT01-03: ABBV-621: A best-in-class TRAIL-receptor agonist fusion protein that enhances optimal clustering for the treatment of solid and hematologic tumors

Abstract Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily of proteins that play diverse roles in the activation of several intracellular signaling pathways that control cell proliferation, survival, and apoptosis. Activation of the TRAIL pathway has been viewed as an attractive therapeutic approach for the treatment of cancer because of its distinct role in the induction of tumor cell apoptosis. TRAIL can bind as a trimer to membrane-bound or soluble receptors, and only the two closely related cell surface death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) can preferentially trigger the extrinsic pathway of tumor cells, leading to apoptotic cell death. The BCL-2 family member-driven mitochondrial apoptotic pathway can also serve to amplify the extrinsic pathway through further downstream activation of caspases. Given the crosstalk between the extrinsic and intrinsic cell death pathways, several resistance mechanisms have emerged to escape TRAIL-induced apoptosis. These include altered receptor regulation, overexpression of cellular FLICE-like inhibitory protein (cFLIP) that inhibits the proapoptotic activity of the DISC, overexpression of the prosurvival BCL-2 family member proteins, and the inhibitor of apoptosis proteins (IAPs) that directly inhibit caspases. In addition, TRAIL can induce non–cell death signaling pathways (e.g., NF-κB, MAPK, PI3K) to promote tumor cell growth as a potential resistance mechanism. Results of several clinical trials that targeted DR4 and DR5 with first-generation agonistic anti-TRAIL antibodies or human recombinant TRAIL indicated that these agents failed to demonstrate significant improvement in patient progression-free survival compared to standard-of-care therapy. The major contributing factor in this lack of clinical activity is believed to be the suboptimal TRAIL receptor clustering by these agonists. ABBV-621 is a novel, second-generation TRAIL receptor agonist comprising a human IgG1-Fc linked to native single-chain TRAIL-receptor binding domain (scTRAIL-RBD) monomers that are covalently connected by glycosylated linkers, resulting in two sets of trimeric RBDs. ABBV-621 is designed to maximize receptor clustering butdoes not require Fcγ-R-mediated crosslinking for optimal in vivo efficacy, which has been deemed an activity-limiting step for the competitor anti-DR4 and anti-DR5 antibodies in the clinic. In-house studies have demonstrated the requirement for enhanced caspase-8 aggregation into the death-inducing signaling complex (DISC) to induce potent tumor cell death, providing mechanistic insights as to why death receptor agonists originally failed and further distinguishing ABBV-621 from the first-generation agents. ABBV-621 induces dose-dependent apoptotic cell death at sub- to single-digit nanomolar potencies across a large panel (~100) of human hematologic and solid tumor cell lines in vitro. ABBV-621 activity is on-target and mechanism-based as demonstrated by a rapid activation of downstream apoptotic signaling events (cleavage of caspase-8, caspase-3, and PARP). In human tumor xenograft models, ABBV-621 exhibits potent antitumor activity in vivo as a monotherapy and in combination with targeted agents or chemotherapy using xenograft tumors derived from colorectal, lung, leukemia, and lymphoma cell lines. This activity is on-target, mechanism-based, and dose-dependent as indicated by rapid activation of tumor caspase-8 and caspase-3 after a single ascending dose of ABBV-621 in a colorectal carcinoma xenograft model. ABBV-621 exhibits a dose-proportional pharmacokinetic (PK) profile in mice and cynomolgus monkeys, and the projected human half-life is estimated to be ~2 days. PK/pharmacodynamic (PD) assessments estimate that achieving exposure above an efficacious concentration for 4-7 days is sufficient to maintain tumor regressions up to 4-7 weeks. Screens against 95 patient-derived xenograft (PDX) models consisting of 12 different solid tumor types uncovered single-agent activity (regressions) in &amp;gt;50% of all PDXs tested. PDX models can be more reflective of human disease by providing estimation of effects of tumor heterogeneity on ABBV-621 activity. Models that were partially sensitive or completely resistant to treatment were also identified, and collectively these responses are being utilized with associated pre- and post-treatment genomic/proteomic information to further inform potential patient stratification markers. To demonstrate on-target biologic activity in the clinic, proximal and distal target engagement markers will be pursued. In a GLP monkey toxicity study, ABBV-621 was well tolerated with no adverse test item–related findings. The first-in-human (FIH) phase 1/1b study with ABBV-621 will enroll subjects with previously treated advanced solid tumors and hematologic malignancies. The phase 1 objectives will be to establish the safety and tolerability of ABBV-621, as well as to understand the PK properties. Secondary objectives will be to explore target engagement and efficacy biomarkers and to evaluate clinical activity. Citation Format: Susan E. Morgan-Lappe. ABBV-621: A best-in-class TRAIL-receptor agonist fusion protein that enhances optimal clustering for the treatment of solid and hematologic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr DDT01-03. doi:10.1158/1538-7445.AM2017-DDT01-03

Antiproliferative Activity and Effect on GABAA Receptors of Callitrisic Acid Derivatives

AbstractThe semisynthesis and biological activity of the naturally occurring abietane diterpenoids callitrisic acid (4a; 4-epidehydroabietic acid) and callitrisinol (6) are reported. These compounds and jiadifenoic acid C (5) were obtained from methyl callitrisate (4b) isolated from Sandarac resin for biological evaluation and comparison with the biological activities of C4 epimers such as dehydroabietic acid (2a). In particular, the antiproliferative activity against a panel of six representative human solid tumor cell lines (A549, HBL-100, HeLa, SW1573, T-47D, WiDr) and the effect on GABAA receptors (α 1 β 2 γ 2s) were evaluated. The GI50 values were in the range of 3.4–61 µM and the potentiation of IGABA was 269–311% at 100 µM. Callitrisinol (6) was found to be 6.7-fold more potent than the reference etoposide in the WiDr (colon) cancer cell line. The role of the stereogenic center at C4 for antiproliferative and GABAA receptor modulating activities in the dehydroabietane scaffold has thus been revealed.

Indole carboxylic acid esters of melampomagnolide B are potent anticancer agents against both hematological and solid tumor cells

A series of novel, heteroaryl carboxylic acid conjugates of the sesquiterpene melampomagnolide-B (MMB, 3) has been evaluated as antitumor agents against an NCI panel of 64 human hematopoetic and solid tumor cell lines. The indole-3-acrylic acid conjugate 7j and the indole-3-carboxylic acid conjugate 7k were found to be the most potent analogs in the series. Compounds 7j and 7k exhibited remarkable growth inhibition, with GI50 values in the range 0.03–0.30 μM and 0.04–0.28 μM, respectively, against the cell lines in the leukemia sub-panel, and GI50 values of 0.05–0.40 μM and 0.04–0.61 μM, respectively, against 90% of the solid tumor cell lines in the NCI panel. Compound 7a was particularly effective against the sub-panel of breast cancer cell lines with GI50 values in the range <0.01–0.30 μM. Compounds 7j, 7a and its water soluble analog 7p also exhibited potent anticancer activity against rat 9L-SF gliosarcoma cells in culture. Compound 7j was the most potent compound in the series in the M9-ENL1 AML cell assay with a lethal dose concentration EC50 value of 720 nM, and exhibited the greatest cytotoxicity against a collection of primary AML stem cell specimens, which included a specimen that was unresponsive to PTL, affording EC50 values in the range 0.33–1.0 μM in three out of four specimens. The results from this study provide further evidence that analogs of the sesquiterpene MMB can be designed to afford molecules with significantly improved anticancer activity. Thus, both 7j and 7k are considered potential lead molecules in the search for new anticancer agents that can be used as treatments for both hematopoetic and solid tumors.

Efficient synthesis and biological evaluation of new benzopyran-annulated pyrano[2,3-c]pyrazole derivatives

A one-pot method has been described to synthesize benzopyran-annulated pyrano[2,3-c]pyrazoles, effectively by combining O-alkenyloxy/alkynyloxy-acetophenones with various pyrazolones in triethylammonium acetate (TEAA) under microwave irradiation. While combination of O-allyloxy- or O-prenyloxy-acetophenones with pyrazolones occurred efficiently, that of O-propargyloxy-acetophenones was found effective in the presence of ZnO catalyst, via a domino Knoevenagel-hetero-Diels-Alder (DKHDA) reaction. Aminobenzopyran frameworks were also synthesized, after nitro-containing products were reduced in tandem with iron(II) in an acidic medium. The in vitro antiproliferative activity of these compounds was measured and discussed against gram-positive, gram-negative and M. tuberculosis bacteria, fungi, and various representative human solid tumor cell lines, in addition to their ferric reducing antioxidant capability.

Total Synthesis of the Proposed Structure for Aromin and Its Structural Revision.

This paper describes the first total synthesis of the proposed structure for aromin, an annonaceous acetogenin possessing an unusual bis-THF ring system, and its 4S,7R-isomer. The key steps involve an oxidative cyclization of a couple of terminal-diene alcohols and an intermolecular metathesis of an alkenyl tetrahydrofuran with an enone carrying a tetrahydrofuranyl lactone. The spectral data of both samples did not match those of aromin. Re-examination of the NMR data using the CAST/CNMR Structure Elucidator and chemical derivations suggested that the real structure of aromin should be revised to be a tetrahydropyran acetogenin, montanacin D. Cytotoxicities in human solid tumor cell lines for synthetic samples were also evaluated.

Cytotoxic activities of flavonoids from a traditional Mongolian medicinal herb Clematis aethusifolia Turcz.

In the course of our search for antitumour constituents from the traditional Mongolian medicinal herb Clematis aethusifolia Turcz., 11 flavonoids were isolated for the first time from the dried aerial parts of the plant by flash C18 column chromatography, Sephadex LH-20 and reversed phase preparative HPLC. The planar structures of these flavonoids were established based on 1D and 2D NMR and high-resolution mass spectrometry. Compounds 1, 2, 4 and 5 showed moderate cytotoxicity against a panel of five human solid tumour cell lines, including A-375, a human melanoma cell line; SK-OV-3, a human ovarian cancer cell line; A549, a human lung cancer cell line; HCT-15, a human colorectal adenocarcinoma cell line; and SH-SY5Y, a human neuroblastoma cell line (with IC50 values of 20–70 μM). The obtained cytotoxic apigenin and its derivatives may be useful as standard compounds for the quality control of the crude drug and its preparations.

Cytotoxic and Antitumor Activity of some Coumarin Derivatives

Several natural and synthetic coumarins were assayed against different cancer cell lines. Four of them have shown cytotoxicity against a panel of three human solid tumor cell lines (HeLa, T-47D, and WiDr) and a clearly activity/hydrophobicity relationship. Compound 13 proved to be the most active product in all cell lines tested, with values of 8.0 (±0.38) μM against HeLa cells and also able to inhibit Taq DNA polymerase. This dual activity of 13 makes it a candidate to be considered as a "lead" compound in the search for novel antitumor drugs.

Synthesis, characterization, and antitumor evaluation of 4-aminoximidofurazan derivatives

ABSTRACTReactions of 3-amino-4-aminoximidofurazan (AAOF) with Wittig–Horner reagents, trialkylphosphites, trisdialkylaminophosphines as well as the thiating Lawesson and Japanese reagents were studied. Elemental analysis and spectroscopic measurements were in good accord with the structures postulated for the new products. The antitumor activities of certain selected new compounds were screened, in vitro, against a panel of five (liver; HepG2; breast; MCF-7; lung; A549; colon; HCT116; and prostate PC3) human solid tumor cell lines.

Antiproliferative effect of extract from endophytic fungus Curvularia trifolii isolated from the “Veracruz Reef System” in Mexico

Context: It is well known that marine fungi are an excellent source of biologically active secondary metabolites, and by 2011, it was reported that over 400 bioactive metabolites were derived from marine fungi.Objective: This study establishes the basis for future research on antiproliferative compounds of marine endophytes inhabited in the Veracruz Reef System.Materials and methods: Isolation of the 34 fungal strains was carried out by microbiological method from samples of sponges, corals, and other biological material from the Veracruz Reef System. The fungal biomass and broth were separated and extracted with a mixture of solvents MeOH:CHCl3. Characterization and molecular identification of the fungal strains were performed through microbiological methods and the analysis of the ITS-rDNA regions. Antiproliferative activity was tested at a dose of 250 μg/mL on human solid tumor cell lines HBL-100, HeLa, SW1573, T-47D, and WiDr by the SRB assay after 48 h-exposure to the fungal extracts.Results: The extracts from five isolates showed an antiproliferative effect against one or more of the tested cell lines (percentage growth < 50%). The mycelial extract from the isolate LAEE 03 manifested the highest activity against the five cell lines (% PG of 17 HBL-100, 19 HeLa, 23 SW1573, -6 T-47D, and 10 WiDr) and the strain was identified as Curvularia trifolii (Kauffman) Boedijn (Pleosporaceae).Discussion and conclusion: The results obtained indicate that the extract from a marine derived C. trifolii has the antiproliferative effect, thus suggesting that this organism is a good candidate for further analysis of its metabolites.