Psammocindoles A-C: Isolation, Synthesis, and Bioactivity of Indole-γ-lactams from the Sponge Psammocinia vermis.

Psammocindoles A-C (1-3), a new class of indole alkaloids, were isolated from a Psammocinia vermis sponge. By combined spectroscopic analyses, the structures of these compounds were determined to be the indole-γ-lactams derived from three amino acid residues. In addition, an enantiomer psammocindole D (4), and the N-lactam isomers isopsammocindoles A-D (5-8) were also synthesized. These natural products and synthetic analogues were found to significantly stimulate adiponectin secretion in human bone marrow mesenchymal stem cells.

Isocadiolides A-H: Polybrominated Aromatics from a Synoicum sp. Ascidian.

Isocadiolides A-H (1-8) and cadiolide N (9), new polybrominated aromatic compounds, were isolated from a Korean Synoicum sp. ascidian. On the basis of the results of extensive spectroscopic analyses, these compounds possessed tris-bromohydroxyphenyl moieties as a common structural motif, while their cores varied [cyclopentenedione (1-5), dihydrofuran (6 and 7), pyranone (8), and furanone (9)], reflecting different extents of rearrangement and oxidation. Several of these compounds exhibited weak antibacterial activities and moderate abilities to inhibit the microbial enzymes sortase A and isocitrate lyase.

The novel strategy for concurrent chemoradiotherapy by conjugating the apoptotic cell-binding moiety to caspase-3 activated doxorubicin prodrug.

The selective targeting of cytotoxic agents to a tumor has shown limited success by difficulties in identifying the appropriate target molecules, and more importantly, by the phenotypically dynamic nature of the tumor cells and intratumoral heterogeneity. In an attempt to overcome these issues and efficiently deliver cytotoxic drugs to the tumor, we previously reported a strategy termed radiation-induced apoptosis-targeted chemotherapy (RIATC), which utilizes the radiotherapy for intentionally triggering the caspase-3 and in situ amplification of tumor apoptosis by caspase-3 activated prodrug. Herein, we propose an advanced form of RIATC prodrug, AP1-DEVD-S-DOX, that could more actively target to the ligands of radiation-induced tumor cells, which could accumulate more prodrugs, thereby allowing more effective in situ activation and amplification of tumor apoptosis, comparing to RIATC. Indeed, AP1-DEVD-S-DOX was able to exert improved doxorubicin (DOX) delivery to the tumor and anticancer effect than the RIATC prodrug that lacks apoptotic cell-binding property but having a similar degree of off-target distribution in the other organs. Accordingly, AP1-DEVD-S-DOX could be an efficient prodrug for concurrent chemoradiotherapy by selectively delivering doxorubicin to the tumor with less systemic cytotoxicity.

Highly potent monomethyl auristatin E prodrug activated by caspase-3 for the chemoradiotherapy of triple-negative breast cancer.

Despite the emergence of advanced therapeutics such as targeted therapy and immunotherapy in the modern oncology, cytotoxic chemotherapy still remains as the first-line treatment option in a wide range of cancers attributing to its potency. Many endeavors have been made to overcome the toxicity issues of cytotoxic chemotherapy by improving the specific delivery to the tumor, with active tumor targeting being one of the most popular approaches. However, such an approach has been challenged by the intratumor heterogeneity and the lack of valid molecular target in many types of cancer. Here, we introduce a novel albumin-binding prodrug MPD02 that could specifically deliver highly potent cytotoxin monomethyl auristatin E (MMAE) to the tumor as an important component of chemoradiotherapy for the treatment of triple-negative breast cancer (TNBC). MPD02 was synthesized by conjugating MMAE to the C-terminus of the KGDEVD peptide via self-eliminating linker and introducing a maleimide group to the Lys side chain of the peptide. MPD02 was able to bind albumin after administration via maleimide group for an extended circulation time and metabolized into MMAE in tumor-specific manner by reacting with the caspase-3 upregulated in tumor by radiotherapy, exerting a highly potent anticancer effect with good safety profile in two different TNBC xenograft models.

Self-Triggered Apoptosis Enzyme Prodrug Therapy (STAEPT): Enhancing Targeted Therapies via Recurrent Bystander Killing Effect by Exploiting Caspase-Cleavable Linker.

Tumor heterogeneity is associated with the therapeutic failures of targeted therapies. To overcome such heterogeneity, a novel targeted therapy is proposed that could kill tumor populations with diverse phenotypes by delivering nonselective cytotoxins to target-positive cells as well as to the surrounding tumor cells via a recurrent bystander killing effect. A representative prodrug is prepared that targets integrin αvß3 and releases cytotoxins upon entering cells or by caspase-3. This allows the prodrug to kill integrin αvß3-positive cells and upregulate caspase-3, which in turn, activates the prodrug to release a cytotoxin that could subsequently diffuse into and kill the neighboring tumor cells. Apoptotic cells further upregulate and release caspase-3, which activate more prodrugs leading to another round of adjacent cell death and caspase-3 release. Thus, the bystander killing effect could occur repeatedly, leading to augmented and widespread anticancer activity. This strategy provides an avenue that could advance the current targeted therapy.

Asperphenins A and B, Lipopeptidyl Benzophenones from a Marine-Derived Aspergillus sp. Fungus.

Asperphenins A (1) and B (2), novel diastereomeric lipopeptidyl benzophenone metabolites, were isolated from a marine-derived Aspergillus sp. fungus. On the basis of the results of combined spectroscopic analyses, the structures of these compounds were determined to be linear assemblies of three motifs: a hydroxy fatty acid, a tripeptide, and a trihydroxybenzophenone. The absolute configurations were assigned using chemical modifications and electronic circular dichroism (ECD) calculations. The novel compounds exhibited significant cytotoxicity on diverse cancer cells.

Determination and validation of psammaplin A and its derivatives in rat plasma by liquid chromatography-tandem mass spectrometry and its application in pharmacokinetic study.

A liquid chromatography-tandem mass (LC-MS/MS) method was developed for the determination of psammaplin A (PsA) and its newly synthesized derivatives (PsA 107, PsA 109, and PsA 123) in rat plasma using bupropion as an internal standard (IS). The plasma samples were deproteinized with acetonitrile. Chromatographic separation was performed on hydro-RP column (75×2.0mm, 80Å, 4µm) with isocratic elution using 5mM ammonium formate buffer/acetonitrile (30:70, v/v) at a flow rate of 0.4mL/min and the total run time was 5min. Mass spectrometric detection was performed with positive electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode. The ion transitions monitored were m/z 663.2→331.0, 687.2→343.1, 587.3→293.1, 563.3→281.0, and 240.0→184.0 for PsA, PsA 107, PsA 109, PsA 123, and IS, respectively. All analytes showed good linearity over the concentration range of 5.00-5000ng/mL (r(2)≥0.994). The lower limit of quantification was 5ng/mL for PsA and its three PsA derivatives. Within- and between-run precisions (relative standard deviation, RSD) were less than 9.66% and accuracy (relative error, RE) ranged from -9.34% to 7.25%. Established method was successfully applied to the investigation of pharmacokinetic properties of PsA and its derivatives in rats after intravenous administration at a dose of 2mg/kg.

Amino Acid-Derived Metabolites from the Ascidian Aplidium sp.

Four new iodobenzene-containing dipeptides (1-4), a related bromotryptophan-containing dipeptide (5), and an iodophenethylamine (6) were isolated from the ascidian Aplidium sp. collected off the coast of Chuja-do, Korea. The structures of these novel compounds, designated as apliamides A-E (1-5) and apliamine A (6) were determined via combined spectroscopic analyses. The absolute configuration of the amino acid residue in 1 was determined by advanced Marfey's analysis. Several of these compounds exhibited moderate cytotoxicity and significant inhibition against Na+/K+-ATPase (4).

Streptococcus mutans sortase A inhibitory metabolites from the flowers of Sophora japonica.

A new maltol derivative (2) along with three known maltol derivative (1) and flavonol glycosides (3 and 4) were isolated from the dried flowers of Sophora japonica. Based upon the results of combined spectroscopic methods, the structure of new compound (2) was determined to be maltol-3-O-(4'-O-cis-p-coumaroyl-6'-O-(3-hydroxy-3-methylglutaroyl))-ß-glucopyranoside, an isomer of 1. These compounds strongly inhibited the action of sortase A (SrtA) from Streptococcus mutans, a primary etiologic agent of human dental caries. The onset and magnitude of inhibition of the saliva-induced aggregation in S. mutans treated with compound 2 (4×IC50) were comparable to the behavior of untreated srtA-deletion mutant.

Bioactive Metabolites from the Fruits of Psoralea corylifolia.

Twenty-four metabolites, including seven new compounds (1-7), were isolated from the dried fruits of Psoralea corylifolia. On the basis of combined spectroscopic and chemical analysis, the new compounds were determined to be six flavonoids (1-6) and a meroterpenoid (7). The absolute configurations of the natural products obtained, including the previously undetermined 16 and 17, were assigned by several methods, such as NOE spectroscopy, optical rotation, and CD spectroscopy. Several of these compounds exhibited moderate inhibitory activity toward Staphylococcus mutans-derived SrtA (2, 6, and 16) and significant stimulation of SIRT1 activity (2, 3, and 15).

Amino alcohols from the ascidian Pseudodistoma sp.

Seven new amino alcohol compounds, pseudoaminols A-G (1-7), were isolated from the ascidian Pseudodistoma sp. collected off the coast of Chuja-do, Korea. Structures of these new compounds were determined by analysis of the spectroscopic data and from chemical conversion. The presence of an N-carboxymethyl group in two of the new compounds (6 and 7) is unprecedented among amino alcohols. Several of these compounds exhibited moderate antimicrobial activity and cytotoxicity, as well as weak inhibitory activity toward Na+/K+-ATPase.

New benzoxazine secondary metabolites from an arctic actinomycete.

Two new secondary metabolites, arcticoside (1) and C-1027 chromophore-V (2), were isolated along with C-1027 chromophore-III and fijiolides A and B (3-5) from a culture of an Arctic marine actinomycete Streptomyces strain. The chemical structures of 1 and 2 were elucidated through NMR, mass, UV, and IR spectroscopy. The hexose moieties in 1 were determined to be d-glucose from a combination of acid hydrolysis, derivatization, and gas chromatographic analyses. Arcticoside (1) and C-1027 chromophore-V (2), which have a benzoxazine ring, inhibited Candida albicans isocitrate lyase. Chromophore-V (2) exhibited significant cytotoxicity against breast carcinoma MDA-MB231 cells and colorectal carcinoma cells (line HCT-116), with IC50 values of 0.9 and 2.7 µM, respectively.

New cyclic cystine bridged peptides from the sponge Suberites waedoensis.

Two new peptides, chujamides A (1) and B (2), were isolated from the marine sponge Suberites waedoensis, which was collected from Korean waters. Based upon the results of the combined spectroscopic analyses, the structures of these compounds were determined to be proline-riched and cyclic cystine bridged dodeca- and undecapeptides. The absolute configurations of all amino acid residues were determined to be l by advanced Marfey's analysis. The new compounds exhibited weak cytotoxicities against A549 and K562 cell-lines, and compound 2 also demonstrated moderate inhibitory activity against Na⁺/K⁺-ATPase.

Brominated aromatic furanones and related esters from the ascidian Synoicum sp.

Nine new compounds, tris-aromatic furanones (1, 2, 3a, 3b, and 4) and related bis-aromatic diesters (5a, 5b, 6a, and 6b), are described from the ascidian Synoicum sp. collected off the coast of Chuja-do, Korea. The structures of these compounds, designated as cadiolides E and G-I (1-4) and synoilides A and B (5 and 6), were determined by extensive spectroscopic analyses. The absolute configuration at the asymmetric center of cadiolide G (2) was assigned by ECD analysis. Of these new compounds, cadiolide I and the synoilides possess unprecedented carbon skeletons. Several of these compounds exhibited significant inhibition against diverse bacterial strains as well as moderate inhibition against the enzymes sortase A, isocitrate lyase, and Na(+)/K(+)-ATPase.

Beta-carboline alkaloids derived from the ascidian Synoicum sp.

Six ß-carboline alkaloids (1-6) of the eudistomin Y class were isolated from the Korean ascidian Synoicum sp. These compounds were chemically converted to a known compound, eudistomin Y(1) (7) and six new derivatives, designated eudistomins Y(8)-Y(13) (8-13). Several of these natural and synthetic compounds exhibited moderate to significant antimicrobial activity, weak cytotoxic activity, and inhibitory activities toward sortase A, isocitrate lyase, and Na(+)/K(+)-ATPase. Structure-activity relationships were also deduced.