Showing papers by "Susan L. Morris-Natschke published in 2014"

Indole Alkaloid Glycosides From the Aerial Parts of Strobilanthes Cusia

Abstract: Three indole alkaloid glycosides, strobilanthosides A-C (1-3), two known indole alkaloid glucosides (4 and 5), and five phenylethanoid glycosides (8-10) were isolated from the aerial parts of Strobilanthes cusia. The structures of the new compounds were elucidated by spectrometric analysis, and the absolute configurations of 1 and 2 were established by ECD spectrocsopy. N'-β-d-Glucopyranosylindirubin (5) showed weak antibacterial activity (MIC 62.5-125 μM) against Staphylococcus aureus.

Design, synthesis, mechanisms of action, and toxicity of novel 20(s)-sulfonylamidine derivatives of camptothecin as potent antitumor agents

Abstract: Twelve novel 20-sulfonylamidine derivatives (9a-9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chk related DNA damage-response pathway. In xenograft models, 9a demonstrated significant activity without overt adverse effects at 5 and 10 mg/kg, comparable to 3 at 100 mg/kg. Notably, 9a at 300 mg/kg (i.p.) showed no overt toxicity in contrast to 1 (LD50 56.2 mg/kg, i.p.) and 3 (LD50 177.5 mg/kg, i.p.). Intact 9a inhibited Topo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9a is a new class of Topo I inhibitor. 20-Sulfonylamidine 1-derivative 9a merits development as an anticancer clinical trial candidate.

Optimization of 4-(N-Cycloamino)phenylquinazolines as a Novel Class of Tubulin-Polymerization Inhibitors Targeting the Colchicine Site

Abstract: The 6-methoxy-1,2,3,4-tetrahydroquinoline moiety in prior leads 2-chloro- and 2-methyl-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)quinazoline (1a and 1b) was modified to produce 4-(N-cycloamino)quinazolines (4a-c and 5a-m). The new compounds were evaluated in cytotoxicity and tubulin inhibition assays, resulting in the discovery of new tubulin-polymerization inhibitors. 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin- 2(1H)-one (5f), the most potent compound, exhibited high in vitro cytotoxic activity (GI50 1.9-3.2 nM), significant potency against tubulin assembly (IC50 0.77 μM), and substantial inhibition of colchicine binding (99% at 5 μM). In mechanism studies, 5f caused cell arrest in G2/M phase, disrupted microtubule formation, and competed mostly at the colchicine site on tubulin. Compound 5f and N-methylated analogue 5g were evaluated in nude mouse MCF7 xenograft models to validate their antitumor activity. Compound 5g displayed significant in vivo activity (tumor inhibitory rate 51%) at a dose of 4 mg/kg without obvious toxicity, whereas 5f unexpectedly resulted in toxicity and death at the same dose.

Notolutesins A-J, dolabrane-type diterpenoids from the Chinese liverwort Notoscyphus lutescens.

Abstract: Ten new dolabrane-type diterpenoids, notolutesins A–J (1–10), were isolated from the Chinese liverwort Notoscyphus lutescens, along with four known compounds. The structures of the new compounds were established on the basis of extensive spectroscopic data, and that of 1 was confirmed by single-crystal X-ray crystallography. The absolute configuration of 1 was determined by comparing its experimental and calculated electronic circular dichroism spectra. All of the isolates were evaluated for their cytotoxicity against a small panel of human cancer cell lines, and compound 1 exhibited an IC50 value of 6.2 μM against the PC3 human prostate cancer cell line.

Design, synthesis, crystal structure, bioactivity, and molecular docking studies of novel sulfonylamidine-derived neonicotinoid analogs

Abstract: Two novel series of sulfonylamidine-derived neonicotinoid analogues were designed and synthesized via a Cu-catalyzed one pot reaction. The structures of the target compounds were characterized by 1H-NMR, 13C-NMR, HR-MS and the single-crystal structure of 14k was further determined by X-ray diffraction crystallography. In preliminary bioassays, many of the target compounds exhibited significant activity against Tetranychuscinnabarinus (carmine spider mite) and Brevicorynebrassicae (cabbage aphid). Some structural features important for potency were observed, and a model of the ligand–receptor complex was also generated with a molecular docking study using representative active analogues. The molecular binding mode observed at the active site of the nicotinic acetylcholine receptor model should provide useful information for future structure-based design of novel sulfonylamidine-derived neonicotinoid analogues.

Optimization of the antiviral potency and lipophilicity of halogenated 2,6-diarylpyridinamines as a novel class of HIV-1 NNRTIS.

Abstract: Nineteen new halogenated diarylpyridinamine (DAPA) analogues (6a-n and 8a-e) modified on the phenoxy C-ring were synthesized and evaluated for anti-HIV activity and certain drug-like properties. Ten compounds showed high anti-HIV activity (EC50 0.3, LLE >5, LELP <10). With balanced potency and drug-like properties, 8c merits further development as an anti-HIV drug candidate.

Synthesis of novel spin-labeled derivatives of 5-FU as potential antineoplastic agents

Abstract: Chemotherapy is a general treatment option for various cancers, including lung cancer. In order to find compounds with superior bioactivity and less toxicity against lung cancer, novel spin-labeled 5-fluorouracil (5-FU) derivatives (3a–f) were synthesized and evaluated against four human tumor cell lines (A-549, DU-145, KB, and KBvin). Two promising compounds 3d and 3f exhibited IC50 values of 2.76 and 2.38 μM, respectively, against non-small cell lung carcinoma cell line A-549. These compounds were twofold more cytotoxic than 5-FU and less toxic against other tested cell lines. Compound 3f exhibited seven times more selective cytotoxicity against A-549 than 5-FU. Our results suggest that compounds 3d and 3f merit further investigation for development into clinical trial candidates for non-small cell lung cancer.

Toward Synthesis of Third-Generation Spin-Labeled Podophyllotoxin Derivatives Using Isocyanide Multicomponent Reactions.

Abstract: A new generation of spin-labeled podophyllotoxin analogues are synthesized and evaluated for their cytotoxicity against four human cancer cell lines.