Significance Natural products provide the inspiration for most drugs, and marine natural products, in particular, are emerging as promising new therapeutics with targets or mechanisms of action. Pharmacological targeting tubulin dynamics has been a validated strategy cancer therapy decades, yielding structurally diverse derivatives, including paclitaxel, vincristine, maytansine, eribulin, six known different binding sites. We discovered chemical scaffold from cyanobacteria that seventh site....

Abstract The taccalonolides are a class of structurally and mechanistically distinct microtubule-stabilizing agents isolated from Tacca chantrieri. A crucial feature the taxane family microtubule stabilizers is their susceptibility to cellular resistance mechanisms including overexpression P-glycoprotein (Pgp), multidrug protein 7 (MRP7), βIII isotype tubulin. ability four taccalonolides, A, E, B, N, circumvent these was studied. Taccalonolides N were effective in vitro against cell lines...

A total of 24 novel 2,5-diaryl-1,3,4-oxadiazoline analogs combretastatin A-4 (CA-4, 1) were designed, synthesized, and evaluated for biological activities. The compounds represent two structural classes; the Type I class has three methoxy groups on ring II a single group ring. Biological evaluations demonstrate that multiple features control potency. Four compounds, 2-(3′-bromophenyl)-5-(3′′,4′′,5′′-trimethoxyphenyl)-2-acetyl-2,3-dihydro-1,3,4-oxadiazoline (9l),...

Two classes of molecules were designed and synthesized based on a 6-CH3 cyclopenta[d]pyrimidine scaffold pyrrolo[2,3-d]pyrimidine scaffold. The pyrrolo[2,3-d]pyrimidines by reacting ethyl 2-cyano-4,4-diethoxybutanoate acetamidine, which in turn was chlorinated reacted with the appropriate anilines to afford 1 2. cyclopenta[d]pyrimidines obtained from 3-methyladapic acid, followed reaction acetamidine Chlorination afforded (±)-3·HCl−(±)-7·HCl. Compounds (±)-3·HCl had potent antiproliferative...

The cyclic tetrapeptide 1-alaninechlamydocin was purified from a Great Lakes-derived fungal isolate identified as Tolypocladium sp. Although the planar structure previously described, detailed analysis of its spectroscopic data and biological activity are reported here for first time. Its absolute configuration determined using combination ((1)H-(1)H ROESY, ECD, X-ray diffraction) chemical (Marfey's analysis) methods. 1-Alaninechlamydocin showed potent antiproliferative/cytotoxic activities...

The taccalonolides are a class of microtubule stabilizing agents isolated from plants the genus Tacca. In efforts to define their structure-activity relationships, we five new taccalonolides, AC-AF and H2, one fraction an ethanol extract Tacca plantaginea. structures were elucidated using combination spectroscopic methods, including 1D 2D NMR HR-ESI-MS. Taccalonolide AJ, epoxidation product taccalonolide B, was generated by semisynthesis. Five these demonstrated cellular...

Chemotherapy-induced peripheral neuropathy (CIPN) arises from collateral damage to afferent sensory neurons by anticancer pharmacotherapy, leading debilitating neuropathic pain. No effective treatment for CIPN exists, short of dose-reduction which worsens cancer prognosis. Here, we report that stimulation nicotinamide phosphoribosyltransferase (NAMPT) produced robust neuroprotection in an aggressive model utilizing the frontline drug, paclitaxel (PTX). Daily rats with first-in-class NAMPT...

Some of the most valuable antimalarial compounds, including quinine and artemisinin, originated from plants. While these drugs have served important roles over many years for treatment malaria, drug resistance has become a widespread problem. Therefore, critical need exists to identify new compounds that efficacy against drug-resistant malaria strains. In current study, extracts prepared plants readily obtained local sources were screened activity Plasmodium falciparum. Bioassay-guided...

Microtubule-targeting agents (MTAs), including both microtubule stabilizers and destabilizers are highly effective chemotherapeutic drugs used in the treatment of solid tumors hematologic malignancies. In addition to shared ability all MTAs block cell cycle progression, growing evidence shows that different this class can also have mechanistically distinct effects on nonmitotic microtubule-dependent cellular processes, signaling transport. Herein, we test biologic hypothesis triple-negative...

Eribulin is a microtubule destabilizer used in the treatment of triple-negative breast cancer (TNBC). and other targeted drugs, such as taxanes, have shared antimitotic effects, but differ their mechanism disruption, leading to diverse effects on cellular signaling trafficking. Herein, we demonstrate that eribulin unique from paclitaxel its ability enhance expression immunogenic cytokine interferon beta (IFNβ) combination with STING agonists both immune cells TNBC models, including profound...

The general amino acid permease, Gap1p, of Saccharomyces cerevisiae transports all naturally occurring acids into yeast cells for use as a nitrogen source. Previous studies have shown that nonubiquitinateable form the Gap1p(K9R,K16R), is constitutively localized to plasma membrane. Here, we report transport activity Gap1p(K9R,K16R) can be rapidly and reversibly inactivated at membrane by presence mixtures. Surprisingly, also find addition most single lethal Gap1p(K9R,K16R)-expressing cells,...

The taccalonolides are a unique class of microtubule stabilizers that do not bind directly to tubulin. Three new taccalonolides, Z, AA, and AB, along with two known compounds, R T, were isolated from Tacca chantrieri integrifolia. Taccalonolide structures determined by 1D 2D NMR methods. biological activities the as well A, B, E, N, R, evaluated. All nine display stabilizing activity, but profound differences in antiproliferative potencies noted, IC(50) values ranging low nanomolar range for...

Microtubule stabilizers suppress microtubule dynamics and, at the lowest antiproliferative concentrations, disrupt function of mitotic spindles, leading to arrest and apoptosis. At slightly higher these agents cause formation multiple asters with distinct morphologies elicited by different stabilizers. We tested hypothesis that two classes stabilizing drugs, taxanes taccalonolides, aster structures due, in part, differential effects on dynamics. Paclitaxel taccalonolides suppressed...

Mass-spectrometry-based metabolomics and molecular phylogeny data were used to identify a metabolically prolific strain of

Abstract Glioblastoma (GB) is the most common and aggressive malignant brain tumor in adults, with a median survival of ~15 months. Given poor currently approved treatments, new therapies are urgently needed. Microtubule-targeting agents (MTAs) represent one successful first-line for cancers, however, inability MTAs to cross blood-brain barrier (BBB) limits their use central nervous system (CNS) cancers. The development novel good BBB penetrance, decreased toxicity, an ability overcome...

The high capacity general amino acid permease, Gap1p, in Saccharomyces cerevisiae is distributed between the plasma membrane and internal compartments according to availability of acids. When levels are low, Gap1p localized where it imports available acids from medium. sufficient imported, at endocytosed newly synthesized delivered vacuole; both sorting steps require ubiquitination. Although has been suggested that identical trans-acting factors ubiquitin acceptor sites involved processes,...

Evidence shows that the anticancer effects of microtubule targeting agents are not due solely to their antimitotic activities but also ability impair microtubule-dependent oncogenic signalling.The on regulators TGF-β-induced epithelial-to-mesenchymal transition (EMT) were evaluated in breast cancer cell lines using high content imaging, gene and protein expression, siRNA-mediated knockdown chromatin immunoprecipitation.Microtubule rapidly differentially alter expression Snail Slug, key...

It has been proposed that one of the mechanisms taxane-site ligand-mediated tubulin activation is modulation structure a switch element (the M-loop) from disordered form in dimeric to folded helical microtubules. Here, we used covalent ligands, including cyclostreptin, gain further insight into this mechanism. The crystal cyclostreptin-bound reveals binding βHis229, but no stabilization M-loop. capacity cyclostreptin induce microtubule assembly compared other agents demonstrates induction...

Triple-negative breast cancers (TNBC) are aggressive and heterogeneous that lack targeted therapies. We implemented a screening program to identify new leads for subgroups of TNBC using diverse cell lines with different molecular drivers. Through this program, we identified an extract from Calotropis gigantea caused selective cytotoxicity in BT-549 cells as compared four other lines. Bioassay-guided fractionation the yielded nine cardenolides responsible activity. These included eight known...

During our efforts to identify biologically active compounds from Red Sea marine invertebrates, a new compound, latrunculin U (1), was identified the sponge Negombata magnifica along with latrunculins A (2), B (3), and 16-epi-latrunculin (4). The structures of were elucidated based on combination comprehensive 1D 2D NMR analyses high-resolution mass spectral determinations. antiproliferative potency each compound in HeLa cells evaluated, they had IC50 values ranging 0.31 1.64 μM. activities...