Showing papers by "Susan L. Morris-Natschke published in 2019"

Discovery of an Oleanolic Acid/Hederagenin-Nitric Oxide Donor Hybrid as an EGFR Tyrosine Kinase Inhibitor for Non-Small-Cell Lung Cancer.

Abstract: Natural triterpenoids, such as oleanolic acid (OA) and hederagenin, display anti-lung cancer effects, and nitric oxide (NO) is associated with some oncogenic signaling pathways. Accordingly, 17 OA/hederagenin-NO donor hybrids were designed, synthesized, and evaluated against tumor cells. The most potent compound, 13, significantly inhibited the proliferation of five tumor cell lines (IC50 4.6-5.2 μM), while hederagenin inhibited the growth of only A549 tumor cells (IC50 > 10 μM). Furthermore, compound 13 showed stronger inhibitory effects on EGFR-LTC kinase activity (IC50 0.01 μM) than hederagenin (IC50 > 20 μM) and inhibited the proliferation of gefitinib-resistant H1975 (IC50 8.1 μM) and osimertinib-resistant H1975-LTC (IC50 7.6 μM) non-small-cell lung cancer (NSCLC) cells. Moreover, compound 13 produced the most NO in H1975 tumor cells, which indicated that NO may play a synergistic role. Collectively, compound 13, a novel hederagenin-NO donor hybrid with a different chemical structure from those of the current FDA-approved EGFR-targeted anti-NSCLC drugs, may be a promising lead compound for the treatment of NSCLC expressing gefitinib-resistant EGFR with a T790 M mutation or osimertinib-resistant EGFR-LTC with an L858R/T790M/C797S mutation. This work should shed light on the discovery of new anti-NSCLC drugs targeting EGFR from natural products.

Kalshinoids A-F, Anti-inflammatory Sesquiterpenes from Kalimeris shimadae.

Abstract: In a study of the potential anti-inflammatory constituents from Kalimeris shimadae, six new sesquiterpenes, kalshinoids A-F (1-6), together with 21 known compounds (7-27), were isolated. The structures and absolute configurations of the new compounds were discerned from extensive spectroscopic analysis, and the absolute configurations of kalshinoids A, B, E, and F were established by ECD calculations. Furthermore, the identified compounds were tested for anti-inflammatory activity as assessed by inhibition of tumor necrosis factor-alpha (TNF-α) in THP-1 cells. Three sesquiterpenes [kalshinoid F, 4(15)-eudesmen-1β,7,11-triol, and 4α,10α,11-trihydroxy-1βH,5βH-guai-7(8)-ene] reduced levels of TNF-α in lipopolysaccharide-stimulated THP-1 cells in a concentration-dependent manner and were more potent than dexamethasone. These natural sesquiterpenes merit further investigation as possible anti-inflammatory agents.

Carbazole Alkaloids from Clausena anisum-olens: Isolation, Characterization, and Anti-HIV Evaluation.

Abstract: Two new carbazole alkaloids (1,2) and six known carbazole alkaloids (3-8) were isolated from Clausena anisum-olens. Their structures were elucidated based on extensive spectroscopic analysis. All isolated compounds (1-8) were evaluated for their anti-HIV effects on virus replication in MT-4 lymphocytes infected by HIV-1NL4-3 Nanoluc-sec virus, and new carbazole alkaloid 1 exhibited anti-HIV activity with an EC50 value of 2.4 μg/mL and SI of 7.1.

Synthesis and Structure-Activity Relationship Correlations of Gnidimacrin Derivatives as Potent HIV-1 Inhibitors and HIV Latency Reversing Agents.

Abstract: Currently, due to the HIV latency mechanism, the search continues for effective drugs to combat this issue and provide a cure for AIDS. Gnidimacrin activates latent HIV-1 replication and inhibits HIV-1 infection at picomolar concentrations. This natural diterpene was able to markedly reduce the latent HIV-1 DNA level and the frequency of latently infected cells. Therefore, gnidimacrin is an excellent lead compound, and its anti-HIV potential merits further investigation. Twenty-nine modified gnidimacrin derivatives were synthesized and evaluated in assays for HIV replication and latency activation to establish which molecular structures must be maintained and which can tolerate changes that may be needed for better pharmacological properties. The results indicated that hydroxyl substituents at C-5 and C-20 are essential, while derivatives modified at 3-OH with aromatic esters retain anti-HIV replication and latent activation activities. The half-lives of the potent GM derivatives are over 20 h, which implies that they are stable in the plasm even though they contain ester linkages. The established structure-activity relationship should be useful in the development of gnidimacrin or structurally related compounds as clinical trial candidates.

Antiproliferative Aspidosperma-Type Monoterpenoid Indole Alkaloids from Bousigonia mekongensis Inhibit Tubulin Polymerization.

Abstract: Monoterpenoid indole alkaloids are structurally diverse natural products found in plants of the family Apocynaceae. Among them, vincristine and its derivatives are well known for their anticancer activity. Bousigonia mekongensis, a species in this family, contains various monoterpenoid indole alkaloids. In the current study, fourteen known aspidosperma-type monoterpenoid indole alkaloids (1⁻14) were isolated and identified from a methanol extract of the twigs and leaves of B. mekongensis for the first time. Among them, compounds 3, 6, 9, and 13 exhibited similar antiproliferative activity spectra against A549, KB, and multidrug-resistant (MDR) KB subline KB-VIN cells with IC50 values ranging from 0.5⁻0.9 μM. The above alkaloids efficiently induced cell cycle arrest at the G2/M phase by inhibiting tubulin polymerization as well as mitotic bipolar spindle formation. Computer modeling studies indicated that compound 7 likely forms a hydrogen bond (H-bond) with α- or β-tubulin at the colchicine site. Evaluation of the antiproliferative effects and SAR analysis suggested that a 14,15-double bond or 3α-acetonyl group is critical for enhanced antiproliferative activity. Mechanism of action studies demonstrated for the first time that compounds 3, 4, 6, 7, and 13 efficiently induce cell cycle arrest at G2/M by inhibiting tubulin polymerization by binding to the colchicine site.

Danazol mediates collateral sensitivity via STAT3/Myc related pathway in multidrug-resistant cancer cells

Abstract: Multidrug resistance presents an obstacle in cancer treatment. Among numerous combative strategies, collateral sensitivity (CS) drugs have opened a new avenue to defeat cancer by exploiting selective toxicity against multidrug-resistant (MDR) cancer. In the present study, a clinically used synthetic steroid hormone, danazol, was investigated for its CS properties and cytotoxic mechanisms. Compared with natural hormones, danazol possessed a stronger selective cytotoxicity against MDR cancer cells. Danazol induced the arrest of MDR cancer cells at the G2/M phase and caspase-8-related early apoptosis. Furthermore, in MDR cancer cells, danazol reduced STAT3 phosphorylation as well as the expression of STAT3-regulated genes involved in cell survival, such as c-Myc, CDC25, and CDK1. Danazol also upregulated the cell cycle inhibitor p21 in MDR cancer cells. Supporting the experimental results, docking studies have revealed that danazol can likely bind favourably with STAT3. Taken together, our results suggest that danazol exerts a CS effect by inhibiting the STAT3 pathway in MDR cancer cells and thus provides a possible solution for MDR cancers.

New Dammarane-type Saponins from Gynostemma pentaphyllum.

Abstract: Six new dammarane-type saponins, gypenosides CP1-6 (1–6), along with 19 known compounds 7–25, were isolated and characterized from the aerial parts of Gynostemma pentaphyllum. Among these compounds, eight dammarane-type saponins, 2, 5, 6, 7, 11, 12, 13, and 15, exhibited the greatest antiproliferative effects against two human tumor cell lines (A549 and HepG2).

One-step templated synthesis of chiral organometallic salicyloxazoline complexes.

Abstract: The general approach to the synthesis of metal complexes begins with ligand synthesis, followed by ligand reaction with metal salts to afford organometallic complexes. Our research group first reported a one-pot multicomponent synthesis of chiral oxazolinyl–zinc complexes, in the presence of a large amount of ZnCl2 (0.4–2.6 equiv.), with the yields of some products reaching 90%. Our prior strategy was extended to use copper, cobalt, nickel, manganese, palladium or platinum salts as the third component. The one-step method used 1.0 equivalent of a metal salt, such as M(OAc)2·nH2O or MCl2·nH2O (M: Cu, Co, Ni, Pd or Pt, n = 1, 2 or 4), as a reagent to generate chiral salicyloxazoline complexes 1–8 in the reaction of 2-cyanophenol with different d- and l-amino alcohols. Complexes 1–8 were obtained using a one-pot method with a sequential strategy. The reaction outcome was demonstrated for three-component reactions between metal salts, amino alcohols and 2-hydroxybenzonitrile to afford organometallic complexes in good yields (65–95%).

Correction to: One-step templated synthesis of chiral organometallic salicyloxazoline complexes

Abstract: Following publication of the original article [1], the authors reported an error in Schemes 1 and 2 and repeated line in subsection “Bis(ligand) nickel(II) chelate (NiL12)”.