Amyrisins A–C, <i>O</i>-Prenylated Flavonoids from <i>Amyris madrensis</i>

Three new <i>O</i>-prenylated flavonoids, amyrisins A–C (<b>1</b>–<b>3</b>), were isolated from the leaves and twigs of <i>Amyris madrensis</i>, along with the known compound polygamain (<b>4</b>). The structures of <b>1</b>–<b>3</b> were elucidated on the basis of the analysis of spectroscopic data interpretation. Amyrisins B (<b>2</b>) and C (<b>3</b>) showed moderate cytotoxicity against PC-3 and DU 145 prostate cancer cells with IC₅₀ values of 17.5 and 23 μM, respectively, while amyrisin A (<b>1</b>) did not show any cytotoxicity at the highest concentration tested, 50 μM. Polygamain (<b>4</b>) exhibited potent antiproliferative and microtubule-depolymerizing activities

Synthetic Reactions with Rare Taccalonolides Reveal the Value of C‑22,23 Epoxidation for Microtubule Stabilizing Potency

The taccalonolides are microtubule stabilizers isolated from plants of the genus <i>Tacca</i>. Taccalonolide AF is 231 times more potent than the major metabolite taccalonolide A and differs only by the oxidation of the C-22,23 double bond in A to an epoxy group in AF. In the current study, 10 other rare natural taccalonolides were epoxidized and in each case epoxidation improved potency. The epoxidation products of taccalonolide T and AI were the most potent, with IC₅₀ values of 0.43 and 0.88 nM, respectively. These potent taccalonolides retained microtubule stabilizing effects, and T-epoxide demonstrated antitumor effects in a xenograft model of breast cancer. Additional reactions demonstrated that reduction of the C-6 ketone resulted in an inactive taccalonolide and that C-22,23 epoxidation restored its activity. These studies confirm the value of C-22,23 epoxidation as an effective strategy for increasing the potency of a wide range of structurally diverse taccalonolide microtubule stabilizers

Hydrolysis Reactions of the Taccalonolides Reveal Structure–Activity Relationships

The taccalonolides are microtubule stabilizers isolated from plants of the genus <i>Tacca</i> that show potent in vivo antitumor activity and the ability to overcome multiple mechanisms of drug resistance. The most potent taccalonolide identified to date, AJ, is a semisynthetic product generated from the major plant metabolite taccalonolide A in a two-step reaction. The first step involves hydrolysis of taccalonolide A to generate taccalonolide B, and then this product is oxidized to generate an epoxide group at C-22–C-23. To generate sufficient taccalonolide AJ for in vivo antitumor efficacy studies, the hydrolysis conditions for the conversion of taccalonolide A to B were optimized. During purification of the hydrolysis products, we identified the new taccalonolide AO (<b>1</b>) along with taccalonolide I. When the same hydrolysis reaction was performed on a taccalonolide E-enriched fraction, four new taccalonolides, assigned as AK, AL, AM, and AN (<b>2</b>–<b>5</b>), were obtained in addition to the expected product taccalonolide N. Biological assays were performed on each of the purified taccalonolides, which allowed for increased refinement of the structure–activity relationship of this class of compounds

An Iridoid Glucoside and the Related Aglycones from <i>Cornus florida</i>

A new iridoid glucoside, cornusoside A (<b>1</b>), and four new natural product iridoid aglycones, cornolactones A–D (<b>2</b>–<b>5</b>), together with 10 known compounds were isolated from the leaves of <i>Cornus florida</i>. The structures of compounds <b>1</b>–<b>5</b> were established by interpretation of their spectroscopic data. Cornolactone B (<b>3</b>) is the first natural <i>cis</i>-fused tricyclic dilactone iridoid containing both a five- and a six-membered lactone ring. A biosynthesis pathway is proposed for cornolactones C (<b>4</b>) and D (<b>5</b>), the C-6 epimers of compounds <b>1</b>–<b>3</b>

The Bat Flower: A Source of Microtubule-Destabilizing and -Stabilizing Compounds with Synergistic Antiproliferative Actions

The biosynthesis of secondary metabolites provides higher plants with mechanisms of defense against microbes, insects, and herbivores. One common cellular target of these molecules is the highly conserved microtubule cytoskeleton, and microtubule-targeting compounds with insecticidal, antifungal, nematicidal, and anticancer activities have been identified from plants. A new retro-dihydrochalcone, taccabulin A, with microtubule-destabilizing activity has been identified from the roots and rhizomes of <i>Tacca</i> species. This finding is notable because the microtubule-stabilizing taccalonolides are also isolated from these sources. This is the first report of an organism producing compounds with both microtubule-stabilizing and -destabilizing activities. A two-step chemical synthesis of taccabulin A was performed. Mechanistic studies showed that taccabulin A binds within the colchicine site on tubulin and has synergistic antiproliferative effects against cancer cells when combined with a taccalonolide, which binds to a different site on tubulin. Taccabulin A is effective in cells that are resistant to many other plant-derived compounds. The discovery of a natural source that contains both microtubule-stabilizing and -destabilizing small molecules is unprecedented and suggests that the synergistic action of these compounds was exploited by nature long before it was discovered in the laboratory

Taccalonolide Microtubule Stabilizers Generated Using Semisynthesis Define the Effects of Mono Acyloxy Moieties at C‑7 or C‑15 and Disubstitutions at C‑7 and C‑25

The taccalonolides are a unique class of microtubule stabilizers isolated from <i>Tacca</i> spp. that have efficacy against drug-resistant tumors. Our previous studies have demonstrated that a C-15 acetoxy taccalonolide, AF, has superior in vivo antitumor efficacy compared to AJ, which bears a C-15 hydroxy group. With the goal of further improving the in vivo efficacy of this class of compounds, we semisynthesized and tested the biological activities of 28 new taccalonolides with monosubstitutions at C-7 or C-15 or disubstitutions at C-7 and C-25, covering a comprehensive range of substituents from formic acid to anthraquinone-2-carbonyl chloride. The resulting taccalonolide analogues with diverse C-7/C-15/C-25 modifications exhibited IC₅₀ values from 2.4 nM to >20 μM, allowing for extensive in vitro structure–activity evaluations. This semisynthetic strategy was unable to provide a taccalonolide with improved therapeutic window due to hydrolysis of substituents at C-7 or C-15 regardless of size or steric bulk. However, two of the most potent new taccalonolides, bearing isovalerate modifications at C-7 or C-15, demonstrated potent and highly persistent antitumor activity in a drug-resistant xenograft model when administered intratumorally. This study demonstrates that targeted delivery of the taccalonolides to the tumor could be an effective, long-lasting approach to treat drug-resistant tumors

Taccalonolide Microtubule Stabilizers Generated Using Semisynthesis Define the Effects of Mono Acyloxy Moieties at C‑7 or C‑15 and Disubstitutions at C‑7 and C‑25

The taccalonolides are a unique class of microtubule stabilizers isolated from <i>Tacca</i> spp. that have efficacy against drug-resistant tumors. Our previous studies have demonstrated that a C-15 acetoxy taccalonolide, AF, has superior in vivo antitumor efficacy compared to AJ, which bears a C-15 hydroxy group. With the goal of further improving the in vivo efficacy of this class of compounds, we semisynthesized and tested the biological activities of 28 new taccalonolides with monosubstitutions at C-7 or C-15 or disubstitutions at C-7 and C-25, covering a comprehensive range of substituents from formic acid to anthraquinone-2-carbonyl chloride. The resulting taccalonolide analogues with diverse C-7/C-15/C-25 modifications exhibited IC₅₀ values from 2.4 nM to >20 μM, allowing for extensive in vitro structure–activity evaluations. This semisynthetic strategy was unable to provide a taccalonolide with improved therapeutic window due to hydrolysis of substituents at C-7 or C-15 regardless of size or steric bulk. However, two of the most potent new taccalonolides, bearing isovalerate modifications at C-7 or C-15, demonstrated potent and highly persistent antitumor activity in a drug-resistant xenograft model when administered intratumorally. This study demonstrates that targeted delivery of the taccalonolides to the tumor could be an effective, long-lasting approach to treat drug-resistant tumors

DataSheet1_A cost-effective o-toulidine-based Schiff base as an efficient sorbent for metal ion uptake from aqueous and soil samples: Synthesis, antimicrobial, and acute toxicity analyses.docx

Heavy metals create serious health problems, so the practical implementation and development of low-cost sorbent materials to remove heavy metals from the ecosystem is a worldwide issue. The purpose of this study is to find a low-cost ligand that has the potential to adsorb heavy metals from aqueous and soil samples and also has biological potential. For this, a Schiff base, dimeric o-toluidine (SBL), has been synthesized through condensation, characterized by spectroscopic analysis, and had its biological activities measured. We also studied its adsorption efficiency through a batch technique to remove Zn(II), Co(II), and Cu(II) from aqueous and soil samples under different conditions such as metal ion concentration, pH, contact time, and SBL concentration. The adsorption potential of SBL was analyzed by the Langmuir and Freundlich adsorption isotherms. The values of correlation coefficients revealed that the Freundlich isotherm elucidated results that were more appropriable than the Langmuir model. Adsorption equilibrium was established in 90 min for aqueous samples and in 1,440 min for soil samples. For the maximum adsorption of all metals, the optimum pH was 8, and it showed a capacity to remove 77 to 95 percent of metals from the samples. The maximum adsorption capacity (qmax) of SBL were 75.75, 62.50, and 9.17 mg g-1 in the case of Cu(II), Zn(II), and Co(II) ions, respectively, from aqueous samples and 10.95, 64.10, and 88.49 mg g-1 in the case of Zn(II), Cu (II), and Co(II), respectively, from soil samples. The effectiveness of SBL in the sorption of the selected metals was found to be Cu+2 > Zn+2 > Co+2 for aqueous samples and Co+2 > Cu+2 > Zn+2 for soil samples. The antimicrobial activity of SBL was also investigated. The results revealed that SBL showed moderate inhibitory activity against Staphylococcus dysentria, C. albican, and Aspergillus niger, whereas it exhibited weak activity against S. aureus, P. aureginosa, K. pneumoniae, P. vulgaris, and E.coli when compared to Fluconazole and Ciprofloxacin as the standard. Acute toxicity of the synthesized compound was measured through its daily oral administration with various doses ranging from 0.1 to 1,000 mg/kg of the mice’s body weights. Even at the dose of 1,000 mg/kg, the SBL showed no mortality or any type of general behavioral change in the treated mice. Based on preparation cost, metal removal capacity, toxicity, and antimicrobial activities, SBL is an excellent sorbent and should be studied at pilot scale levels. </p

Texas Native Plants Yield Compounds with Cytotoxic Activities against Prostate Cancer Cells

There remains a critical need for more effective therapies for the treatment of late-stage and metastatic prostate cancers. Three Texas native plants yielded three new and three known compounds with antiproliferative and cytotoxic activities against prostate cancer cells with IC₅₀ values in the range of 1.7–35.0 μM. A new sesquiterpene named espadalide (<b>1</b>), isolated from <i>Gochnatia hypoleuca</i>, had low micromolar potency and was highly effective in clonogenic assays. Two known bioactive germacranolides (<b>2</b> and <b>3</b>) were additionally isolated from <i>G. hypoleuca. Dalea frutescens</i> yielded two new isoprenylated chalcones, named sanjuanolide (<b>4</b>) and sanjoseolide (<b>5</b>), and the known sesquiterpenediol verbesindiol (<b>6</b>) was isolated from <i>Verbesina virginica</i>. Mechanistic studies showed that <b>1</b>–<b>4</b> caused G₂/M accumulation and the formation of abnormal mitotic spindles. Tubulin polymerization assays revealed that <b>4</b> increased the initial rate of tubulin polymerization, but did not change total tubulin polymer levels, and <b>1</b>–<b>3</b> had no effects on tubulin polymerization. Despite its cytotoxic activity, compound <b>6</b> did not initiate changes in cell cycle distribution and has a mechanism of action different from the other compounds. This study demonstrates that new compounds with significant biological activities germane to unmet oncological needs can be isolated from Texas native plants