Showing papers by "Susan L. Morris-Natschke published in 2017"

In Vivo and Mechanistic Studies on Antitumor Lead 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one and Its Modification as a Novel Class of Tubulin-Binding Tumor-Vascular Disrupting Agents.

Abstract: 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one (2), a promising anticancer lead previously identified by us, inhibited tumor growth by 62% in mice at 1.0 mg/kg without obvious signs of toxicity. Moreover, compound 2 exhibited extremely high antiproliferative activity in the NIH-NCI 60 human tumor cell line panel, with low to sub-nanomolar GI50 values (10-10 M level). It also showed a suitable balance between aqueous solubility and lipophilicity, as well as moderate metabolic stability in vivo. Mechanistic studies using Mayer's hematoxylin and eosin and immunohistochemistry protocols on xenograft tumor tissues showed that 2 inhibited tumor cell proliferation, induced apoptosis, and disrupted tumor vasculature. Moreover, evaluation of new synthetic analogues (6a-6t) of 2 indicated that appropriate 2-substitution on the quinazoline ring could enhance antitumor activity and improve druglike properties. Compound 2 and its analogues with a 4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one scaffold thus represent a novel class of tubulin-binding tumor-vascular disrupting agents (tumor-VDAs) that target established blood vessels in tumors.

Vitepyrroloids A-D, 2-Cyanopyrrole-Containing Labdane Diterpenoid Alkaloids from the Leaves of Vitex trifolia.

Abstract: Vitepyrroloids A–D (1–4), four new 2-cyano-substituted pyrrole-ring-containing labdane diterpenoids, were isolated from the leaves of Vitex trifolia. Their structures were elucidated based on spectroscopic data analysis. The absolute configuration of compound 1 was determined by X-ray diffraction. Compounds 1–4 are unprecedented labdane diterpenoids featuring a 2-cyano-substituted pyrrole ring. Compound 1 showed cytotoxic activity against a human nasopharyngeal carcinoma cell line (CNE1) with an IC50 value of 8.7 μM.

Design, Synthesis and Structure-Activity Relationships of (±)-Isochaihulactone Derivatives.

Abstract: Z-K8 (2), the racemic form of isochaihulactone (1), previously showed significant antitumor effects in A549 and LNCaP tumor-bearing mice. In the present study, 17 derivatives of 2 were designed, synthesized and evaluated for their anti-proliferative activity against four human tumor cell lines. All new derivatives exhibited high potency against A549 and P-glycoprotein (P-gp)-overexpressing KB-VIN. One of our new derivatives exhibited greater activity against three tested tumor cells (A549, KB, and KB-VIN) than 2, and induced cell cycle arrest in the G2/M phase. Moreover, SAR conclusions were first established for this series of compounds. Our study clearly identified a structural feature that should be retained for good activity and also a moiety that can tolerate various modifications and, thus, is ideal for further changes.