Development of a Novel Class of Tubulin Inhibitor from Desmosdumotin B with a Hydroxylated Bicyclic B‑Ring

A series of newly synthesized hydroxylated analogues of triethyldesmosdumotin B (TEDB) with a bicyclic B-ring exhibited a significantly different mode of action for affecting microtubule dynamics and spindle formation but had the same antiproliferative activity spectrum, including activity against multidrug-resistant tumors. These analogues efficiently induced cell cycle arrest at prometaphase and caused formation of immature multipolar spindles. 6′-Hydroxyl TEDB-TB (<b>8</b>) disrupted bipolar spindle formation but had a negligible effect on interphase microtubules. On the basis of the predicted binding modes of the new compounds with tubulin dimer, compound <b>4</b> forms three hydrogen bonds (H-bonds) only with α-tubulin at the colchicine site; in contrast, <b>8</b> forms H-bonds with both α- and β-tubulin. We predict that, when a compound/ligand, such as <b>8</b>, forms H-bonds to both α- and β-tubulins, spindle formation is disrupted more than the dynamics of interphase microtubules. This result may reflect the well-known greater dynamicity of spindle microtubules as compared with interphase microtubules

Antitumor Agents. 293. Nontoxic Dimethyl-4,4′-dimethoxy-5,6,5′,6′-dimethylenedioxybiphenyl-2,2′-dicarboxylate (DDB) Analogues Chemosensitize Multidrug-Resistant Cancer Cells to Clinical Anticancer Drugs

Novel dimethyl-4,4′-dimethoxy-5,6,5′,6′-dimethylenedioxybiphenyl-2,2′-dicarboxylate (DDB) analogues were designed and synthesized to improve their chemosensitizing action on KBvin (vincristine-resistant nasopharyngeal carcinoma) cells, a multidrug resistant cell line overexpressing P-glycoprotein (P-gp). Structure–activity relationship analysis showed that aromatic and bulky aliphatic side chains at the 2,2′-positions effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as paclitaxel (TAX), vincristine (VCR), and doxorubicin (DOX). DDB derivatives <b>16</b> and <b>23</b> showed 5–10 times more effective reversal ability than verapamil (VRP) for TAX and VCR. Analogue <b>6</b> also exhibited five times greater chemosensitizing effect against DOX than VRP. Importantly, no cytotoxicity was observed by the active DDB analogues against both non-MDR and MDR cells, suggesting that DDB analogues serve as novel lead compounds for the development of chemosensitizers to overcome the MDR phenotype. The mechanism of action studies demonstrated that effective inhibition of P-glycoprotein by DDB analogues dramatically elevated the cellular concentration of anticancer drugs

(−)-Neocaryachine, an Antiproliferative Pavine Alkaloid from <i>Cryptocarya laevigata</i>, Induces DNA Double-Strand Breaks

Twelve benzylisoquinoline alkaloids, including pavine and phenanthroindolizidine types, were isolated from a MeOH/CH₂Cl₂ extract of <i>Cryptocarya laevigata</i> (stem bark) through bioactivity-guided fractionation for antitumor effects. Selected compounds were evaluated for antiproliferative activity against five human tumor cell lines, including a multidrug-resistant subline. Since more common 2,3,8,9-tetrasubstituted pavine alkaloids, such as crychine (<b>3</b>), exhibit very mild or no cytotoxicity, this compound type has not been well investigated for antitumor activity. Thus, this report is the first discovery of a 7-hydroxylated pavine alkaloid, (−)-neocaryachine (<b>1</b>), to demonstrate strong antiproliferative activity, with IC₅₀ values of 0.06 to 0.41 μM against five tested tumor cell lines, including an MDR subline. Further mechanism of action studies revealed that <b>1</b> impacts the cellular S-phase by inducing DNA double-strand breaks

Corymbulosins D–H, 2‑Hydroxy- and 2‑Oxo-clerodane Diterpenes from the Bark of <i>Laetia corymbulosa</i>

A bioactive CH₃OH–CH₂Cl₂ (1:1) extract of the bark of <i>Laetia corymbulosa</i> provided five new clerodane diterpenes with an isozuelanin skeleton, designated as corymbulosins D–H (<b>1</b>–<b>5</b>), as well as the known corymbulosins B (<b>6</b>) and C (<b>7</b>), for which the relative configurations were not previously determined. The structures of <b>1</b>–<b>5</b> were characterized on the basis of 1D and 2D NMR spectroscopic and HRMS analysis. The absolute configurations of all isolated compounds <b>1</b>–<b>7</b> were verified through chemical methods, including modified Mosher esterifications or oxidation of the hydroxy group at C-2, ECD experiments, and spectroscopic data comparison. The isolated compounds were evaluated for antiproliferative activity against a small panel of human cancer cell lines

Kleinhospitine E and Cycloartane Triterpenoids from <i>Kleinhovia hospita</i>

A novel cycloartane triterpenoid alkaloid, kleinhospitine E (<b>1</b>), six new cycloartane triterpenoids (<b>2</b>–<b>7</b>), three known cycloartane triterpenoids (<b>8</b>–<b>10</b>), and taraxerone (<b>11</b>) were isolated from a methanol extract of <i>Kleinhovia hospita</i>. Their structures were elucidated by 1D- and 2D-NMR spectroscopy as well as HRMS analysis. The absolute configurations of all isolated compounds were determined from their ECD spectra by comparison with theoretical values. Kleinhospitine E (<b>1</b>) is the first cycloartane alkaloid possessing an unusual γ-lactam with an oxopropylidene side chain. Compounds <b>2</b>, <b>3</b>, and <b>6</b> were assigned as cycloartane triterpenoids with a 9α,10α-cyclopropyl ring, which is found rarely among naturally occurring compounds, while <b>4</b> and <b>5</b> were established as isomers of compound <b>3</b> containing a 21,23-diacetal side chain. Biological evaluation revealed that compounds <b>4</b> and <b>9</b> exhibited more potent antiproliferative activities against a multidrug-resistant tumor cell line compared with its parent chemosensitive cell line. Furthermore, compound <b>6</b> exhibited submicromolar anti-HIV activity

Corymbulosins I–W, Cytotoxic Clerodane Diterpenes from the Bark of <i>Laetia corymbulosa</i>

The isolation studies of a crude MeOH/CH₂Cl₂ (1:1) extract (N005829) of the bark of <i>Laetia corymbulosa</i> yielded 15 new clerodane diterpenes, designated corymbulosins I–W (<b>1</b>–<b>15</b>), as well as four known diterpenes, <b>16</b>–<b>19</b>. The structures of <b>1</b>–<b>15</b> were characterized on the basis of extensive 1D and 2D NMR and HRMS analyses. The absolute configurations of newly isolated compounds <b>1</b>–<b>15</b>, as well as known <b>16</b>–<b>19</b>, which were reported previously with only relative configurations, were determined through ECD experiments, X-ray analysis, chemical methods, including Mosher esterification, and comparison of their spectroscopic data. The isolated compounds were evaluated for cytotoxicity against human cancer cell lines. Flow cytometric and immunocytochemical observations of cells treated with cytotoxic clerodanes demonstrated that the chromatin was fragmented and dispersed with formation of apoptotic microtubules

Corymbulosins I–W, Cytotoxic Clerodane Diterpenes from the Bark of <i>Laetia corymbulosa</i>

The isolation studies of a crude MeOH/CH₂Cl₂ (1:1) extract (N005829) of the bark of <i>Laetia corymbulosa</i> yielded 15 new clerodane diterpenes, designated corymbulosins I–W (<b>1</b>–<b>15</b>), as well as four known diterpenes, <b>16</b>–<b>19</b>. The structures of <b>1</b>–<b>15</b> were characterized on the basis of extensive 1D and 2D NMR and HRMS analyses. The absolute configurations of newly isolated compounds <b>1</b>–<b>15</b>, as well as known <b>16</b>–<b>19</b>, which were reported previously with only relative configurations, were determined through ECD experiments, X-ray analysis, chemical methods, including Mosher esterification, and comparison of their spectroscopic data. The isolated compounds were evaluated for cytotoxicity against human cancer cell lines. Flow cytometric and immunocytochemical observations of cells treated with cytotoxic clerodanes demonstrated that the chromatin was fragmented and dispersed with formation of apoptotic microtubules

Dual-Functional <i>abeo</i>-Taxane Derivatives Destabilizing Microtubule Equilibrium and Inhibiting NF-κB Activation

Taxchinin A, with a 11(15→1)-<i>abeo</i>-taxane skeleton, is a major, but inactive taxoid contained in leaves of Taxus chinensis. In our design of dual-functional antitumor <i>abeo</i>-taxane derivatives, two fragments from antitumor agents with different molecular targets (the <i>N</i>-acyl-3′-phenylisoserine side chain from the antimitotic agent paclitaxel and an α,β-unsaturated carbonyl system from NF-κB inhibitors) were incorporated into the scaffold of taxchinin A. The resulting compounds displayed broad inhibitory effects against proliferation of tumor cell lines, with notable selectivity toward colon cancer, melanoma, and renal cancer, when evaluated in the NCI-60 human tumor cell line screening panel. On the basis of the NCI-60 assay data, structure–activity relationship (SAR) correlations were elucidated. Mechanistic studies indicated that this new compound type can both destabilize microtubules and inhibit NF-κB activation, thereby inducing tumor cell apoptosis. This first report of the dual-functional taxoid-core compounds thus provides new opportunities for future drug development based on natural axoid scaffolds

Taburnaemines A–I, Cytotoxic Vobasinyl-Iboga-Type Bisindole Alkaloids from <i>Tabernaemontana corymbosa</i>

Nineteen vobasinyl-ibogan-type bisindole alkaloids, including nine new compounds, taburnaemines A–I (<b>1</b>–<b>9</b>), were isolated from the twigs and leaves of <i>Tabernaemontana corymbosa</i>. The structures and absolute configurations of the new alkaloids were determined by a combination of MS, NMR, and ECD analyses. Alkaloids <b>1</b>–<b>5</b> contain a rare 1,3-oxazinane moiety in the vobasinyl unit, while <b>6</b> has an uncommon 1,3-oxazolidine moiety in the iboga unit. The absolute configurations of alkaloid <b>1</b> and the known alkaloid tabernaecorymbosine A (<b>10</b>) were confirmed by single-crystal X-ray diffraction analysis. All of the bisindole alkaloids, except <b>2</b> and 16′-decarbomethoxy­tabernaecorymbosine A (<b>14</b>), showed antiproliferative activity (IC₅₀ 2.6–9.8 μM) against several human cancer cell lines, including A-549, MDA-MB-231, MCF-7, KB, and P-glycoprotein-overexpressing multidrug-resistant KB cells. The preliminary structure–activity relationship correlations are also discussed

Taburnaemines A–I, Cytotoxic Vobasinyl-Iboga-Type Bisindole Alkaloids from <i>Tabernaemontana corymbosa</i>

Nineteen vobasinyl-ibogan-type bisindole alkaloids, including nine new compounds, taburnaemines A–I (<b>1</b>–<b>9</b>), were isolated from the twigs and leaves of <i>Tabernaemontana corymbosa</i>. The structures and absolute configurations of the new alkaloids were determined by a combination of MS, NMR, and ECD analyses. Alkaloids <b>1</b>–<b>5</b> contain a rare 1,3-oxazinane moiety in the vobasinyl unit, while <b>6</b> has an uncommon 1,3-oxazolidine moiety in the iboga unit. The absolute configurations of alkaloid <b>1</b> and the known alkaloid tabernaecorymbosine A (<b>10</b>) were confirmed by single-crystal X-ray diffraction analysis. All of the bisindole alkaloids, except <b>2</b> and 16′-decarbomethoxy­tabernaecorymbosine A (<b>14</b>), showed antiproliferative activity (IC₅₀ 2.6–9.8 μM) against several human cancer cell lines, including A-549, MDA-MB-231, MCF-7, KB, and P-glycoprotein-overexpressing multidrug-resistant KB cells. The preliminary structure–activity relationship correlations are also discussed