Validation of Cadherin HAV6 Peptide in the Transient Modulation of the Blood-Brain Barrier for the Treatment of Brain Tumors

This work is licensed under a Creative Commons Attribution 4.0 International License.The blood-brain barrier (BBB) poses a major obstacle by preventing potential therapeutic agents from reaching their intended brain targets at sufficient concentrations. While transient disruption of the BBB has been used to enhance chemotherapeutic efficacy in treating brain tumors, limitations in terms of magnitude and duration of BBB disruption exist. In the present study, the preliminary safety and efficacy profile of HAV6, a peptide that binds to the external domains of cadherin, to transiently open the BBB and improve the delivery of a therapeutic agent, was evaluated in a murine brain tumor model. Transient opening of the BBB in response to HAV6 peptide administration was quantitatively characterized using both a gadolinium magnetic resonance imaging (MRI) contrast agent and adenanthin (Ade), the intended therapeutic agent. The effects of HAV6 peptide on BBB integrity and the efficacy of concurrent administration of HAV6 peptide and the small molecule inhibitor, Ade, in the growth and progression of an orthotopic medulloblastoma mouse model using human D425 tumor cells was examined. Systemic administration of HAV6 peptide caused transient, reversible disruption of BBB in mice. Increases in BBB permeability produced by HAV6 were rapid in onset and observed in all regions of the brain examined. Concurrent administration of HAV6 peptide with Ade, a BBB impermeable inhibitor of Peroxiredoxin-1, caused reduced tumor growth and increased survival in mice bearing medulloblastoma. The rapid onset and transient nature of the BBB modulation produced with the HAV6 peptide along with its uniform disruption and biocompatibility is well-suited for CNS drug delivery applications, especially in the treatment of brain tumors

Four new lanostane triterpenoids featuring extended π-conjugated systems from the stems of Kadsura coccinea

Abstract Four new 14(13 → 12)-abeolanostane triterpenoids featuring extended π-conjugated systems, kadcoccitanes E–H (1–4), were obtained from the stems of Kadsura coccinea through using a HPLC − UV-guided approach. Their structural and configurational determination was accomplished through extensive spectroscopic analysis coupled with quantum chemical calculations. Kadcoccitanes E–H were tested for their cytotoxic activities against five human tumor cell lines (HL-60, A-549, SMMC-7721, MDA-MB-231, SW-480) but none of them exhibited activities at the concentration 40 μM. Graphical Abstrac

Adenanthin, a Natural ent-Kaurane Diterpenoid Isolated from the Herb Isodon adenantha Inhibits Adipogenesis and the Development of Obesity by Regulation of ROS

Adenanthin, a natural ent-kaurane diterpenoid extracted from the herb Isodon adenantha, has been reported to increase intracellular reactive oxygen species in leukemic and hepatocellular carcinoma cells. However, the function and mechanism of the compound in adipogenesis and the development of obesity is still unknown. In this study, we demonstrated that adenanthin inhibited adipogenesis of 3T3-L1 and mouse embryonic fibroblasts, and the underlying mechanism included two processes: a delayed mitotic clonal expansion via G0/G1 cell cycle arrest by inhibiting the RB-E2F1 signaling pathway and a reduced C/EBPβ signaling by inhibiting the expression and activity of C/EBPβ during mitotic clonal expansion. Furthermore, adenanthin significantly reduced the growing body weight and adipose tissue mass during high-fat diet-inducing obesity of mice, indicating the beneficial effects of adenanthin as a potential agent for prevention of obesity

Schinortriterpenoids with Identical Configuration but Distinct ECD Spectra Generated by Nondegenerate Exciton Coupling

Ten schinortriterpenoids with biogenetically related lancischiartane scaffolds, including the first 3-norlancischiartane (1) with unusual configuration inversions occurring at C-1 and C-10, were isolated from Schisandra lancifolia. Unusual ECD curve patterns observed in 6-8 were confirmed to be caused by nondegenerate exciton coupling, suggesting that ECD spectrum empirical comparison should be used with caution in configuration determination. Additionally, structure revision of 2, originally proposed as arisanlactone A, was completed using NMR computation and X-ray diffraction analysis

Synthesis of Novel <i>ent</i>-Kaurane-Type Diterpenoid Derivatives Effective for Highly Aggressive Tumor Cells

We have designed and synthesized 6 ent-Kaurane-type diterpenoid derivatives containing &#945;,&#946;-unsaturated ketone moieties. In vitro, activity was evaluated against three human tumor cell lines and a rat myogenic cell line (HepG2, NSCLC-H292, SNU-1040, L6) by MTT assay. All the tested compounds exhibited comparable or higher activity than DDP and eriocalyxin B. Compounds 16, 17 and 18 are promising anti-tumor leads due to their cytotoxic potencies and higher selectivity, with SI values of 161.06, 47.80 and 128.20, respectively

Schinortriterpenoids with Identical Configuration but Distinct ECD Spectra Generated by Nondegenerate Exciton Coupling

Ten schinortriterpenoids with biogenetically related lancischiartane scaffolds, including the first 3-norlancischiartane (<b>1</b>) with unusual configuration inversions occurring at C-1 and C-10, were isolated from <i>Schisandra lancifolia</i>. Unusual ECD curve patterns observed in <b>6</b>–<b>8</b> were confirmed to be caused by nondegenerate exciton coupling, suggesting that ECD spectrum empirical comparison should be used with caution in configuration determination. Additionally, structure revision of <b>2</b>, originally proposed as arisanlactone A, was completed using NMR computation and X-ray diffraction analysis

Isoscoparins R and S, two new <i>ent</i>-clerodane diterpenoids from <i>Isodon scoparius</i>

<p>Two new <i>ent</i>-clerodane diterpenoids, named isoscoparins R and S (<b>1</b> and <b>2</b>), were isolated from the aerial parts of <i>Isodon scoparius</i>. Their structures were characterized mainly by analyzing the NMR and HRESIMS data, and the relative configuration of compound <b>1</b> was determined by single-crystal X-ray diffraction. Compound <b>2</b> showed weak activity as an autophagic inhibitor.</p

7α,20-Epoxy-<i>ent</i>-kaurane Diterpenoids from the Aerial Parts of <i>Isodon pharicus</i>

A phytochemical investigation of an ethyl acetate extract of the aerial parts of <i>Isodon pharicus</i> led to the isolation of 21 new 7α,20-epoxy-<i>ent</i>-kaurane diterpenoids, pharicins C–W (<b>1</b>–<b>21</b>), and 29 known (<b>22</b>–<b>50</b>) analogues. The structural characterization of <b>1</b>–<b>21</b> and assignment of their relative configurations were accomplished by spectroscopic data interpretation, while the structures of <b>1</b> and <b>16</b> were confirmed by X-ray crystallography. The absolute stereostructure of <b>1</b> was confirmed by electronic circular dichroism data analysis. Twenty-five of the diterpenoids were screened for their cytotoxic activities against a panel of tumor cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW-480. Compounds <b>11</b>, <b>16</b>, <b>38</b>, and <b>48</b> exhibited inhibitory activities against these tumor cell lines with IC₅₀ values ranging from 1.01 to 9.62 μM, while <b>2</b>, <b>15</b>, <b>29</b>, and <b>47</b> exhibited moderate cytotoxic potency