RESUMO
Seriniquinone was isolated as a melanoma-selective anti-cancer agent from a culture broth of the marine-derived bacterium Serinicoccus marinus CNJ927 in 2014. It targets the unique small protein, dermcidin, which affects the drug resistance of cancer cells. Due to its significant activity against cancer cells, particularly melanoma, and its unique target, seriniquinone has been developed as a new pharmacophore. However, it has the disadvantage of poor solubility in drug discovery research, which needs to be resolved. A new seriniquinone glycoside (1) was synthesized by the biological transformation of seriniquinone using the deep sea-derived bacterium Bacillus licheniformis KDM612. Compound 1 exhibited selective anti-cancer activity against melanoma, similar to seriniquinone, and was 50-fold more soluble in DMSO than seriniquinone.
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Antineoplásicos , Bacillus licheniformis , Glicosídeos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Glicosídeos/farmacologia , Glicosídeos/química , Glicosídeos/isolamento & purificação , Bacillus licheniformis/metabolismo , Humanos , Biotransformação , Solubilidade , QuinonasRESUMO
To improve optic nerve function in a patient with progressive visual dysfunction, performing early decompressive and debulking surgery for a metastatic tumor located in the optic canal is essential. The endoscopic endonasal approach could be a practical and effective alternative for lesions in the inferomedial part of the optic canal. A 66-year-old man with a right visual eye field deficit had multiple lesions in the pineal gland, occipital lobe, and right inferomedial optic canal. The optic nerve was distorted by a tumor compressing against the falciform ligament. Although a systemic examination suggested the presence of primary lung cancer, the patient only complained of progressive visual impairment in the right eye. We planned surgery with endoscopic transethmoidal and transsphenoidal approaches to restore visual function and make a pathological diagnosis. During the procedure, we drilled the sella floor, tuberculum sellae, and optic canal and successfully removed the tumor underneath the dura mater. The patient's visual function improved rapidly following surgery, and no complications were observed, such as cerebrospinal fluid leakage. After confirming the pathological diagnosis, the patient subsequently received whole-brain radiotherapy. The endoscopic endonasal skull base approach to the optic canal region could be a practical alternative for treating symptomatic metastatic tumors.
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BACKGROUND: Bifocal germ cell tumors, with primarily identical tissue composition, occur concurrently in the neurohypophyseal and pineal regions. OBSERVATIONS: A 16-year-old male patient exhibited increased intracranial pressure symptoms, with concurrent tumors in the pineal and neurohypophyseal regions, causing obstructive hydrocephalus. His serum human chorionic gonadotropin level was elevated, measuring 506.6 mIU/mL. Upon gross endoscopic examination, the pineal tumor appeared white, whereas the neurohypophyseal tumor appeared red and hemorrhagic. Because of the limited sample size of the latter, a frozen section biopsy was feasible only for the pineal lesion, which indicated the presence of a germinoma. Subsequently, carboplatin and etoposide were administered, resulting in the reduction of the pineal tumor, but no effect was observed in the neurohypophyseal tumor. Histopathological analysis confirmed the pineal lesion as a germinoma, whereas the neurohypophyseal lesion was an embryonal carcinoma. Thus, the treatment was altered to ifosfamide, carboplatin, and etoposide (ICE), leading to a response in both tumors. The patient underwent three additional cycles of ICE therapy and high-dose chemotherapy, followed by whole craniospinal irradiation, achieving complete remission. LESSONS: Although most bifocal germ cell tumors share the same histological tissue, occasional differences may arise, necessitating separate biopsies for accurate assessment.
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Nectriatide 1a, a naturally occurring cyclic tetrapeptide, has been reported to a potentiator of amphotericin B (AmB) activity. In order to elucidate its structure-activity relationships, we synthesized nectriatide derivatives with different amino acids in solution-phase synthesis and evaluated AmB-potentiating activity against Candida albicans. Among them, C-and N-terminal protected linear peptides were found to show the most potent AmB-potentiating activity.
Assuntos
Anfotericina B , Antifúngicos , Anfotericina B/química , Antifúngicos/química , Candida albicans , Peptídeos , Testes de Sensibilidade MicrobianaRESUMO
Schwannomas are benign capsular tumors originating from Schwann cells. Although the majority are sporadic, they also occur within tumor predisposition syndromes, such as neurofibromatosis type 2, schwannomatosis, and Carney complex. Since the 5th edition of the World Health Organization(WHO)Classification of Tumors of the Central Nervous System was published, the description of grades has changed from Roman numerals to Arabic numerals. However, as in the 4th edition, it is still a WHO grade 1 benign tumor. There are several other subtypes of schwannomas in addition to the conventional type, and five subtypes have been specifically described in the 5th edition. "Melanocytic Schwannoma" in the 4th edition is now called "malignant melanotic nerve sheath tumor" in the 5th edition and is classified as a different tumor from schwannoma. Although the 5th edition places greater emphasis on genetic diagnoses, it is not essential for diagnosing schwannomas, and histological and clinical diagnoses remain equally crucial. Furthermore, after publication of the 5th edition in September 2022, an international consensus group renamed "neurofibromatosis type 2" as "NF2-related schwannomatosis." This article describes the shifts between the 4th to the 5th edition of the WHO Classification of Tumors of the Central Nervous System, along with additional clarifications, and offers the latest insights into treatment modalities for schwannomas and NF2.
Assuntos
Neoplasias do Sistema Nervoso Central , Neurilemoma , Neurofibromatose 2 , Humanos , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/genética , Neurilemoma/diagnóstico , Organização Mundial da SaúdeRESUMO
Gliomas are the most prevalent primary tumor of the central nervous system. Despite advances in imaging technologies, neurosurgical techniques, and radiotherapy, a cure for high-grade glioma remains elusive. Several groups have reported that protein tyrosine phosphatase receptor type Z (PTPRZ) is highly expressed in glioblastoma, and that targeting PTPRZ attenuates tumor growth in mice. PTPRZ is modified with diverse glycan, including the PTPRZ-unique human natural killer-1 capped O-mannosyl core M2 glycans. However, the regulation and function of these unique glycans are unclear. Using CRISPR genome-editing technology, we first demonstrated that disruption of the PTPRZ gene in human glioma LN-229 cells resulted in profoundly reduced tumor growth in xenografted mice, confirming the potential of PTPRZ as a therapeutic target for glioma. Furthermore, multiple glycan analyses revealed that PTPRZ derived from glioma patients and from xenografted glioma expressed abundant levels of human natural killer-1-capped O-Man glycans via extrinsic signals. Finally, since deficiency of O-Man core M2 branching enzyme N-acetylglucosaminyltransferase IX (GnT-IX) was reported to reduce PTPRZ protein levels, we disrupted the GnT-IX gene in LN-229 cells and found a significant reduction of glioma growth both in vitro and in the xenograft model. These results suggest that the PTPR glycosylation enzyme GnT-IX may represent a promising therapeutic target for glioma.
Assuntos
Glioma , N-Acetilglucosaminiltransferases , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores , Animais , Humanos , Camundongos , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Glioma/fisiopatologia , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Polissacarídeos/metabolismo , Linhagem Celular Tumoral , Feminino , Camundongos SCID , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/deficiência , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/metabolismo , Técnicas de Silenciamento de GenesRESUMO
Gliomas are among the most common tumors of the central nervous system and include highly malignant subtypes, such as glioblastoma, which are associated with poor prognosis. Effective treatments are therefore urgently needed. Despite the recent advances in neuroimaging technologies, differentiating gliomas from other brain diseases such as multiple sclerosis remains challenging in some patients, and often requires invasive brain biopsy. Protein tyrosine phosphatase receptor type Z (PTPRZ) is a heavily glycosylated membrane protein that is highly expressed in the central nervous system. Several reports analyzing mouse tumor models suggest that PTPRZ may have potential as a therapeutic target for gliomas. A soluble cleaved form of PTPRZ (sPTPRZ) in the cerebrospinal fluid is markedly upregulated in glioma patients, making it another promising diagnostic biomarker. Intriguingly, PTPRZ is also involved in the process of remyelination in multiple sclerosis. Indeed, lowered PTPRZ glycosylation by deletion of the glycosyltransferase gene leads to reduced astrogliosis and enhanced remyelination in mouse models of demyelination. Here, we review the expression, molecular structure, and biological roles of PTPRZ. We also discuss glioma and demyelinating diseases, as well as the pathological role of PTPRZ and its application as a diagnostic marker and therapeutic target.
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Doenças do Sistema Nervoso Central , Glioma , Esclerose Múltipla , Animais , Proteínas de Transporte/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Proteínas Tirosina Fosfatases/metabolismo , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/metabolismoRESUMO
Seriniquinone was originally isolated as a melanoma-selective anti-cancer agent from a culture broth of marine bacteria. Pharmacological studies on its selectivity and unique target are ongoing. A new dihydronaphthothiophene (1) was synthesized by the biological transformation of seriniquinone using marine-derived actinomycete Streptomyces albogriseolus OM27-12, and its derivatives (2-4) were chemically synthesized. Compounds 1-4 exhibited selective cytotoxic activity against melanoma and improved solubility.
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Actinobacteria/metabolismo , Antibióticos Antineoplásicos/isolamento & purificação , Antibióticos Antineoplásicos/farmacologia , Streptomyces/química , Actinobacteria/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células Jurkat , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
KEY MESSAGE: An organomercurial phenylmercury activates AtPCS1, an enzyme known for detoxification of inorganic metal(loid) ions in Arabidopsis and the induced metal-chelating peptides phytochelatins are essential for detoxification of phenylmercury. Small thiol-rich peptides phytochelatins (PCs) and their synthases (PCSs) are crucial for plants to mitigate the stress derived from various metal(loid) ions in their inorganic form including inorganic mercury [Hg(II)]. However, the possible roles of the PC/PCS system in organic mercury detoxification in plants remain elusive. We found that an organomercury phenylmercury (PheHg) induced PC synthesis in Arabidopsis thaliana plants as Hg(II), whereas methylmercury did not. The analyses of AtPCS1 mutant plants and in vitro assays using the AtPCS1-recombinant protein demonstrated that AtPCS1, the major PCS in A. thaliana, was responsible for the PheHg-responsive PC synthesis. AtPCS1 mutants cad1-3 and cad1-6, and the double mutant of PC-metal(loid) complex transporters AtABCC1 and AtABCC2 showed enhanced sensitivity to PheHg as well as to Hg(II). The hypersensitivity of cad1-3 to PheHg stress was complemented by the own-promoter-driven expression of AtPCS1-GFP. The confocal microscopy of the complementation lines showed that the AtPCS1-GFP was preferentially expressed in epidermal cells of the mature and elongation zones, and the outer-most layer of the lateral root cap cells in the meristematic zone. Moreover, in vitro PC-metal binding assay demonstrated that binding affinity between PC and PheHg was comparable to Hg(II). However, plant ionomic profiles, as well as root morphology under PheHg and Hg(II) stress, were divergent. These results suggest that PheHg phytotoxicity is different from Hg(II), but AtPCS1-mediated PC synthesis, complex formation, and vacuolar sequestration by AtABCC1 and AtABCC2 are similarly functional for both PheHg and Hg(II) detoxification in root surficial cell types.
Assuntos
Aminoaciltransferases , Proteínas de Arabidopsis , Arabidopsis , Mercúrio , Aminoaciltransferases/genética , Aminoaciltransferases/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Cádmio/metabolismo , Glutationa/metabolismo , Íons/metabolismo , Mercúrio/metabolismo , Mercúrio/toxicidade , Fitoquelatinas/metabolismoRESUMO
For a better understanding of metal-ligand interaction and its function in cells, we developed an easy, sensitive, and high-throughput method to quantify ligand-metal(loid) binding affinity under physiological conditions by combining ligand-attached affinity beads and inductively coupled plasma-optical emission spectrometry (ICP-OES). Glutathione (GSH) and two phytochelatins (PC2 and PC3, small peptides with different numbers of free thiols) were employed as model ligands and attached to hydrophilic beads. The principle of the assay resembles that of affinity purification of proteins in biochemistry: metals binding to the ligand on the beads and the rest in the buffer are separated by a spin column and quantified by ICP-OES. The binding assay using the GSH-attached beads and various metal(loid)s suggested the different affinity of the metal-GSH interactions, in accordance with the order of the Irving-Williams series and the reported stability constants. The binding assay using PC2 or PC3-attached beads suggested positive binding between PCs and Ni(II), Cu(II), Zn(II), Cd(II), and As(III) in accordance with the number of thiols in PC2 and PC3. We then conducted the competition assay using Cd(II), Mn(II), Fe(II), Cu(II), and Zn(II), and the results suggested a better binding affinity of PC2 with Cd(II) than with the essential metals. Another competition assay using PC2 and GSH suggested a robust binding affinity between PCs and Cd(II) compared to GSH and Cd(II). These results suggested the dominance of PC-Cd complex formation in vitro, supporting the physiological importance of PCs for the detoxification of cadmium in vivo. We also discuss the potential application of the assay.
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Glutationa/metabolismo , Metais/metabolismo , Peptídeos/metabolismo , Fitoquelatinas/metabolismo , Compostos de Sulfidrila/metabolismo , Técnicas In Vitro , Ligantes , Ligação ProteicaRESUMO
BACKGROUND: High-grade glioma is the most pervasive and lethal of all brain malignancies. Despite advances in imaging technologies, discriminating between gliomas and other brain diseases such as multiple sclerosis (MS) often requires brain biopsy. Several reports show that protein tyrosine phosphatase receptor Z (PTPRZ) is highly expressed in glioblastoma, and we found that a soluble cleaved form of PTPRZ (sPTPRZ) was present in the cerebrospinal fluid (CSF). The aim of this study was to determine whether the sPTPRZ level in CSF has utility as a diagnostic marker for glioma. METHODS: Microarray datasets from normal brain tissue and brain tumors were obtained from the Gene Expression Omnibus. PTPRZ protein expression in clinical specimens was evaluated by immunohistochemistry. Semiquantitative western blotting was used to measure sPTPRZ levels in CSF samples from patients with glioma, schwannoma, MS, or nontumor disorders. RESULTS: Expression of PTPRZ mRNA and protein was markedly increased in glioblastoma, astrocytoma, oligodendroglioma, and schwannoma tissues compared with control brain tissue. sPTPRZ was present at significantly elevated levels in the CSF of patients with glioma (grades 1-4), but not in patients with schwannoma or MS, compared with the control samples. Receiver operating characteristic curve analysis showed that sPTPRZ in CSF could discriminate between glioma and MS patients (area under the curve 0.9676; P < .0001). CONCLUSIONS: sPTPRZ in CSF is a promising diagnostic biomarker for glioma and could reduce the need for a surgical biopsy.
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A new cytotoxic agent designated as 2-epi-anthracimycin (1) was isolated along with anthracimycin and anthracimycin B (2-demethylanthracimycin) from the culture broth of the marine-derived actinomycete Streptomyces sp. OPMA00631. The structure of 1 was elucidated based on spectroscopic analyses (1D and 2D NMR data and ROESY correlations). Compound 1 exhibited cytotoxicity against Jurkat cells with an IC50 value of 50.5 µM in 20 h. The effect of 1 on the cell cycle distribution of Jurkat cells was investigated. Compound 1 (7.80 µM) increased G1 phase cells from 51.1 to 62.0% and conversely, decreased G2 and M phase cells from 30.7 to 19.3 % in 20 h. At a higher concentration, 1 (250 µM) markedly increased subG1 phase cells (1.9% at 0 h to 16.5% at 20 h), while the proportion of G1 phase cells was maintained (62.3%). These results suggest that 1 exhibits cytotoxicity against Jurkat cells by arresting the cell cycle at the G1 phase.
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Actinobacteria/química , Organismos Aquáticos/química , Citotoxinas/química , Citotoxinas/farmacologia , Policetídeos/química , Policetídeos/farmacologia , Streptomyces/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Células JurkatRESUMO
A new cytotoxic agent designated isomethoxyneihumicin (1 and 2), a mixture of lactam-lactim tautomers, was isolated along with methoxyneihumicin (3) from the culture broth of the marine Nocardiopsis alba KM6-1. The structures of 1 and 2 were elucidated in spectroscopic analyses (1D and 2D NMR data, and ROESY correlations). Isomethoxyneihumicin (15.0 µM) and 3 (15.0 µM) arrested the cell cycle of Jurkat cells at the G2/M phase (66 and 67%) in 12 h. Isomethoxyneihumicin and 3 exhibited cytotoxicity against Jurkat cells with IC50 values of 6.98 and 30.5 µM in 20 h, respectively. These results strongly suggest that isomethoxyneihumicin and 3 exhibit cytotoxicity against Jurkat cells by inhibiting the cell cycle at the G2/M phase.
Assuntos
Actinomycetales/metabolismo , Antineoplásicos/farmacologia , Lactamas/farmacologia , Pirazinas/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/isolamento & purificação , Relação Dose-Resposta a Droga , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Células Jurkat , Lactamas/administração & dosagem , Lactamas/isolamento & purificação , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Pirazinas/administração & dosagem , Pirazinas/isolamento & purificaçãoRESUMO
Vildagliptin is an inhibitor of dipeptidyl peptidase-4 that is used for the treatment of type 2 diabetes mellitus. While vildagliptin can induce hepatic dysfunction in humans, the molecular mechanism has not been determined yet. Recent studies indicated that certain types of microRNA (miRNA) were linking to the development of drug-induced hepatotoxicity. In the present study, therefore, we identified hepatic miRNAs that were highly induced or reduced by the vildagliptin treatment in mice. MiR-222 and miR-877, toxicity-associated miRNAs, were induced 31- and 53-fold, respectively, by vildagliptin in the liver. While a number of miRNAs were significantly regulated by the orally treated vildagliptin in vivo, such regulation was not observed in the vildagliptin-treated HepG2 cells. In addition to the regular two-dimensional (2D) culture, we carried out the three-dimensional (3D) culturing of HepG2 cells. In the 3D-HepG2 cells, a significant reduction of miR-222 was observed compared to the expression level in 2D-HepG2 cells. A slight induction of miR-222 by vildagliptin was observed in the 3D-HepG2 cells, although miR-877 was not induced by vildagliptin even in the 3D-HepG2 cells. Further investigations are needed to overcome the discrepancy in the responsiveness of the miRNA expressions to vildagliptin between in vivo and in vitro.
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Adamantano/análogos & derivados , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , MicroRNAs/metabolismo , Nitrilas/farmacologia , Pirrolidinas/farmacologia , Adamantano/farmacologia , Animais , Técnicas de Cultura de Células , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , VildagliptinaRESUMO
Herein, we report the design and synthesis of the novel 12-membered non-antibiotic macrolide (8R,9S)-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A (EM900), which was found to be a potent anti-inflammatory and/or immunomodulatory agent, capable of promoting monocyte to macrophage differentiation. This molecule shows improved acid stability, does not exhibit any anti-bacterial activity and has relatively low cytotoxicity against THP-1 cells. In addition, one of its analogues, (8R,9S)-4â³,13-O-diacetyl-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A (EM911), was found to be twice as effective as EM900.
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Anti-Inflamatórios/síntese química , Desenho de Fármacos , Eritromicina/análogos & derivados , Eritromicina/química , Fatores Imunológicos/farmacologia , Imunomodulação/efeitos dos fármacos , Macrolídeos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Eritromicina/síntese química , Eritromicina/farmacologia , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Macrolídeos/síntese química , Macrolídeos/química , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura MolecularRESUMO
An effective solid phase synthesis of Argifin, providing subsequent access to effective synthesis of analogues, was developed in 13% overall yield, as well as elucidating structure-activity relationships. The novel acyclic peptide 18b, prepared from a synthetic intermediate of Argifin, was found to be 70 times more potent as an inhibitor of Serratia marcescens chitinases B than Argifin itself.
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Quitinases/antagonistas & inibidores , Peptídeos Cíclicos/síntese química , Peptídeos/síntese química , Sequência de Aminoácidos , Quitinases/metabolismo , Peptídeos/química , Peptídeos/farmacologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Serratia marcescens/enzimologia , Relação Estrutura-AtividadeRESUMO
Total synthesis of a fungal cyclic peptide, malformin C, recently rediscovered as a G2 checkpoint inhibitor was completed. Our synthesis involved a convergent approach with respect to a linear pentapeptide, cyclization, and oxidative disulfide formation.
Assuntos
Antibióticos Antineoplásicos/antagonistas & inibidores , Antibióticos Antineoplásicos/toxicidade , Bleomicina/antagonistas & inibidores , Bleomicina/toxicidade , Fase G2/efeitos dos fármacos , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Divisão Celular/efeitos dos fármacos , Ciclização , Dano ao DNA/efeitos dos fármacos , Dissulfetos/química , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Oxirredução , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Espectrofotometria Infravermelho , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Fungal beauveriolide III (1b), discovered as an inhibitor of lipid droplet accumulation in mouse macrophages and showing antiatherogenic activity in mouse model, consists of l-Phe, l-Ala, d-allo-Ile, and (3S, 4S)-3-hydroxy-4-methyloctanoic acid moieties. A combinatorial library of beauveriolide analogues focusing on l-Ala and d-allo-Ile of 1b was synthesized by combinatorial synthesis. Among them, d-Ala analogues consisting of A{2} improved their solubility, while those with 7{1,3,2},7{2,3,1}, and 7{2,3,2} were 20 times more potent than 1b.
Assuntos
Técnicas de Química Combinatória , Depsipeptídeos/síntese química , Depsipeptídeos/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Esterol O-Aciltransferase/metabolismo , Alanina/química , Aminoácidos/química , Animais , Aterosclerose/prevenção & controle , Depsipeptídeos/química , Modelos Animais de Doenças , Isoleucina/química , Macrófagos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Esterol O-Aciltransferase/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Fungal beauveriolide III (BeauIII, 1b), a cyclodepsipeptide inhibiting acyl-CoA:cholesterol acyltransferase (ACAT) and showing antiatherogenic activity in mouse models, consists of L-Phe, L-Ala, D-allo-Ile, and 3-hydroxy-4-methyloctanoic acid (HMA) moieties, but the stereochemistry of the HMA part has not until now been fully defined. To determine it, four HMA stereoisomers were synthesized and labeled with (S)-(+)-2-(anthracene-2,3-dicarboximido)-1-propyl trifluoromethane sulfonate (AP-OTf), a chiral fluorescent reagent. The derivatives were separated by HPLC and compared with the natural HMA derivative, which was thereby identified as (3S,4S)HMA in BeauIII. Furthermore, the four beauveriolide III isomers ((3S,4S)BeauIII (23a), (3R,4R)BeauIII (23b), (3R,4S)BeauIII (23c), and (3S,4R)BeauIII (23d)) were synthesized, and it was shown that all the spectral data for 23a were identical with those for natural 1b. Isomers 23a and 23d showed potent inhibitory activity of lipid droplet accumulation in macrophages, while the other two isomers caused weak inhibition. Thus, the 3S configuration of BeauIII is important for this activity. Furthermore, 23a and 23d showed rather specific inhibition against the ACAT1 isozyme.