ABSTRACT
Three new plakortides, 7,8-dihydroplakortide E (1), 2, and 10, along with known natural products 3, 4, spongosoritin A (5), 6-8, and plakortide P (9), were isolated from Brazilian specimens of Plakortis angulospiculatus. Compounds 2, 3, 5, and 7-9 displayed cytotoxic activities with IC50 values ranging from 0.2 to 10 µM. Compounds that contained a dihydrofuran ring were generally less active and displayed time dependence in their activity. The activities of compounds 2 and 7-9, carboxylic acids bearing a common six-membered endoperoxide, were higher overall than for compounds 3 and 5. The modes underlying the cytotoxic actions of plakortides 2, 3, 5, 7, and 9 were further investigated using HCT-116 cells. While dihydrofurans 3 and 5 induce a G0/G1 arrest, six-membered peroxides 2, 7, and 9 delivered a G2/M arrest and an accumulation of mitotic figures, indicating a distinctly different antimitotic response. Confocal analysis indicated that microtubules were not altered after treatment with 2, 7, or 9, therein suggesting that the mitotic arrest may be unrelated to cytoskeletal targets. Overall, we find that two related classes of natural products obtained from the same extract offer cytostatic activity, yet they do so through discrete pathways.
Subject(s)
Dioxanes/isolation & purification , Dioxanes/pharmacology , Animals , Antineoplastic Agents/pharmacology , Brazil , Dioxanes/chemistry , Drug Screening Assays, Antitumor , HCT116 Cells , Humans , Molecular Structure , Peroxides/pharmacology , Plakortis , PoriferaABSTRACT
From a small specimen of the marine sponge Plakortis halichondrioides collected in Puerto Rico we have isolated the known unsaturated ester methyl (2Z,6R,8R,9E)-3,6-epoxy-4,6,8-triethyl-2,4,9-dodecatrienoate (1) along with the known cyclic peroxide plakortide F (2). In addition, the structures of two new polyketide endoperoxides, namely, plakortide O (3) and plakortide P (4), were fully characterized by spectroscopic and chemical methods. The absolute stereochemistry of plakortide O methyl ester (3a) has been determined by analysis of the (R)- and (S)-MTPA esters of the acyclic derivative 5 obtained by hydrogenolysis. Plakortide O (3) and plakortide P (4) exhibited potent cytotoxicity in the NCI human cancer screening program, whereas plakortide O methyl ester, 3a, displayed strong antimalarial activity against Plasmodium falciparum [corrected].
Subject(s)
Antimalarials/isolation & purification , Antineoplastic Agents/isolation & purification , Dioxanes/isolation & purification , Porifera/chemistry , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Caribbean Region , Dioxanes/chemistry , Dioxanes/pharmacology , Drug Screening Assays, Antitumor , Molecular Structure , Plasmodium falciparum/drug effects , Puerto Rico , Stereoisomerism , Tumor Cells, Cultured/drug effectsABSTRACT
The bioassay- and spectroscopic-guided fractionation of the antimalarial extract from a Jamaican sponge, Plakortis sp., resulted in the isolation of three metabolites. The previously reported bromoaromatic filiformin (1) was obtained from our sample of Plakortis sp., and the potential origins of this compound are discussed. The peroxide-containing metabolite, plakortide F (2), is a more typical Plakortis metabolite and was shown to exhibit significant activity against Plasmodium falciparum in vitro. The isolation, structure, and bioactivity of a new lactone, plakortone G (3), are also reported.
Subject(s)
Antimalarials/isolation & purification , Bromobenzenes/isolation & purification , Dioxanes/isolation & purification , Lactones/isolation & purification , Porifera/chemistry , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Bromobenzenes/chemistry , Bromobenzenes/pharmacology , Chromatography, High Pressure Liquid , Colonic Neoplasms , Dioxanes/chemistry , Dioxanes/pharmacology , Gas Chromatography-Mass Spectrometry , HIV/drug effects , Hepatitis B , Humans , Jamaica , Lactones/chemistry , Lactones/pharmacology , Leukemia P388 , Lung Neoplasms , Mice , Molecular Structure , Mycobacterium tuberculosis/drug effects , Neoplasms, Unknown Primary , Nuclear Magnetic Resonance, Biomolecular , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Spectrometry, Mass, Electrospray Ionization , Tumor Cells, Cultured/drug effectsABSTRACT
Three new cytotoxic compounds, one a cyclic-peroxide-containing acid (5) and the two others alkylated dihydroxy alpha,beta-unsaturated C22 and C21 acids (6 and 7), were isolated from the marine sponge Plakortis halichondrioides, which was collected off the coast of Jamaica. The structures were elucidated through mass and mainly 1D and 2D nmr spectral analysis. All three acids are cytotoxic against P-388 murine leukemia.