ABSTRACT
Afidopyropen, a novel insecticide, is a derivative of pyripyropene A, which is produced by the filamentous fungus Penicillium coprobium. Afidopyropen has strong insecticidal activity against aphids and is currently used as a control agent of sucking pests worldwide. In this study, we summarized the biological properties and field efficacies of its derivatives against agricultural pests using official field trials conducted in Japan. Afidopyropen showed good residual efficacies against a variety of aphids, whiteflies and other sucking pests under field conditions. Furthermore, toxicological studies revealed its safety profiles against nontarget organisms, such as the honeybee, natural enemies and other beneficial insects, as well as mammals. Thus, afidopyropen is a next-generation agrochemical for crop protection that has a low environmental impact.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemistry , Insecticides/chemistry , Lactones/chemistry , Penicillium/metabolism , Pyridines/metabolism , Sesquiterpenes/metabolism , Animals , Aphids/drug effects , Heterocyclic Compounds, 4 or More Rings/pharmacology , Insecticides/pharmacology , Japan , Lactones/pharmacology , Penicillium/chemistry , Pyridines/chemistry , Sesquiterpenes/chemistryABSTRACT
Pyripyropene A (PP-A), a secondary metabolite produced by filamentous fungi, shows insecticidal activity against agricultural insect pests. Synthesized PP derivatives also show a narrow insecticidal spectrum but high insecticidal activities against such sucking pests. PP-A has a low eco-toxicological impact and satisfies a prerequisite for next-generation insecticides. We investigated the effects of conversion of the 3-pyridyl and α-pyrone rings to other rings, as well as the effects of esterification, dehydration, and oxidization at the C-13 position in natural PP analogues, on the insecticidal activity and spectrum. The conversions of the 3-pyridyl and α-pyrone rings markedly reduced the insecticidal activity with a minimal impact on the spectrum, indicative of an important role for these rings in insecticidal activity. Some derivatives with modified structures at the C-13 position showed a higher inhibitory effect on the motility of canine heartworms and mosquito vectors than did PP-A, suggesting their utility as filaria control drugs.
ABSTRACT
The synthesis and insecticidal activity of a series of pyripyropene derivatives with cyclopropanecarbonyloxy group(s) at the C-1, C-7 and/or C-11 position(s) were investigated to find novel insecticides. Insecticidal screening of the synthesized PP derivatives revealed that derivative 13, which had cyclopropanecarbonyloxy groups at the C-1 and C-11 positions and a hydroxyl group at the C-7 position, showed the highest insecticidal activity against aphids in laboratory tests. Finally, we selected 13 as a new insecticide candidate for agricultural sucking pests, which is now commercialized under the common name afidopyropen.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/pharmacology , Insecticides/chemical synthesis , Insecticides/pharmacology , Lactones/chemical synthesis , Lactones/pharmacology , Animals , Aphids/drug effects , Biological Assay , Molecular StructureABSTRACT
We previously reported the strong insecticidal activity of a microbial secondary metabolite, pyripyropene A (PP-A), against aphids. Pyripyropenes (PPs) have been known to show weak feeding inhibition against lepidopteran pests, but their strong aphicidal activities were first reported in our former study. Here we investigated the details of the insecticidal property of PP-A. Our biological evaluation of PP-A found that it shows high insecticidal activities against some sucking pests, such as whiteflies, as well as aphids, and preferable biological profiles as agricultural insecticides. Furthermore, PP-A controlled aphids well under field conditions.
ABSTRACT
The C-1, C-7, and C-11 positions of pyripyropene A were chemically modified to improve the insecticidal activity. Some derivatives showed higher insecticidal activities against aphids than pyripyropene A. In particular, the derivative 5c, which possesses three cyclopropyl carbonyl groups at the C-1, C-7, and C-11 positions, had excellent insecticidal activity levels in field and laboratory trials.
Subject(s)
Aphids/drug effects , Insecticides/chemical synthesis , Insecticides/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Sesquiterpenes/chemical synthesis , Sesquiterpenes/pharmacology , Animals , Aspergillus fumigatus/metabolism , Mice , Penicillium/metabolism , Pyridines/chemistry , Rats , Sesquiterpenes/chemistryABSTRACT
Approximately 300 microbial natural products in our library were screened for insecticidal activities against three species of agricultural pests, including aphids. Among the several compounds that showed insecticidal activities, pyripyropene A had high aphicidal activity in vivo. Furthermore, in advanced tests, pyripyropene A applications with foliar sprays and soil drenching controlled aphids on cabbage. On the basis of its unique and promising activities, we selected pyripyropene A as the active component of potential insecticides.
Subject(s)
Insecticides/toxicity , Pyridines/toxicity , Sesquiterpenes/toxicity , Animals , Aphids , Brassica , Molecular Structure , Moths , TetranychidaeABSTRACT
Pyripyropenes potently and selectively inhibit acyl-CoA:cholesterol acyltransferase 2 (ACAT-2). Among multiple isomers of pyripyropene (A to R), pyripyropene A (PyA) has insecticidal properties in addition to its growth inhibition properties against human umbilical vein endothelial cells. Based on the predicted biosynthetic gene cluster of pyripyropene A, two genes (ppb8 and ppb9) encoding two acetyltransferases (ATs) were separately isolated and introduced into the model fungus Aspergillus oryzae, using the protoplast-polyethylene glycol method. The bioconversion of certain predicted intermediates in the transformants revealed the manner by which acetylation occurred in the biosynthetic pathway by the products expressed by these two genes (AT-1 and AT-2). The acetylated products detected by high-performance liquid chromatography (HPLC) in the extracts from AT-1 and AT-2 transformant clones were not present in the extract from the transformant clone with an empty vector. The HLPC charts of each bioconversion study exhibited high peaks at 12, 10.5 and 9 min, respectively. Further ultraviolet absorption and mass spectrometry analyses identified the products as PyE, PyO and PyA, respectively. AT-1 acetylated the C-1 of deacetyl-pyripyropene E (deAc-PyE), while AT-2 played an active role in acetylating the C-11 of 11-deAc-PyO and C-7 of deAc-PyA at two different steps of the biosynthetic pathway.
ABSTRACT
Pyripyropenes are potent inhibitors of acyl-CoA:cholesterol acyltransferase, which were initially discovered to be produced by Aspergillus fumigatus. Recently, Penicillium coprobium PF1169 has also found to produce pyripyropene A (PyA), which exhibits insecticidal properties. Pyripyropenes are natural hybrid products of both terpenoid and polyketide origin. In our research, based on data generated using the Genome Sequencer FLX for P. coprobium PF1169, we predicted the biosynthetic gene cluster of PyA by blast analysis comparing with polyketide synthase and prenyltransferase of other species. By screening the genomic fosmid library, nine open reading frames (ppb1 to ppb9) related to the biosynthesis of PyA were deduced. Among them, two cytochrome P450 monooxygenase genes (ppb3 and ppb4) were separately introduced into the model fungus A. oryzae. Bioconversion of certain predicted intermediates in the transformants has elucidated the manner of hydroxylation in the biosynthetic pathway by the expressed products of these two genes (P450-1 and P450-2). That is, P450-1 exhibits monooxygenase activity and plays the hydroxylation role at C-11 of pyripyropene E. While P450-2 plays an active role in the hydroxylation of C-7 and C-13 of pyripyropene O.
Subject(s)
Cytochrome P-450 Enzyme System/genetics , Genes, Bacterial/genetics , Penicillium/genetics , Pyridines/metabolism , Sesquiterpenes/metabolism , Chromosome Mapping , Cloning, Molecular , DNA, Fungal/genetics , Insecticides/metabolism , Molecular Sequence Data , Multigene Family/genetics , Open Reading Frames/geneticsABSTRACT
We report a successful case with pulmonary metastases from lower gingival cancer by a surgical procedure and four cycles of adjuvant chemotherapy including paclitaxel (PTX), cisplatin (CDDP) and 5-fluorouracil (5-FU). A 47-year-old woman underwent chemotherapy with CDDP and 5-FU after an operation for lower gingival squamous cell carcinoma and its neck lymph node metastases. At 4 months from the initial treatment, pulmonary metastatic lesion was resected by video-assisted thoracoscopic surgery (VATS). Fourteen months later, pulmonary metastatic lesion was found and dissected again using VATS. Furthermore, the patient was treated by adjuvant chemotherapy with PTX 135 mg/m(2) over 3 hours on day 1, CDDP 75 mg/m(2)on day 2 and 5-FU 350 mg/m(2)/day by continuous intravenous infusion on day 2 through 5. After that, there is no evidence of pulmonary recurrence for more than six years.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Gingival Neoplasms/drug therapy , Lung Neoplasms/secondary , Lymph Nodes/pathology , Pneumonectomy/methods , Carcinoma, Squamous Cell/secondary , Carcinoma, Squamous Cell/surgery , Chemotherapy, Adjuvant , Cisplatin/administration & dosage , Combined Modality Therapy , Drug Administration Schedule , Female , Fluorouracil/administration & dosage , Gingival Neoplasms/pathology , Gingival Neoplasms/surgery , Humans , Lung Neoplasms/surgery , Lymphatic Metastasis , Middle Aged , Paclitaxel/administration & dosage , Remission Induction , Thoracic Surgery, Video-AssistedABSTRACT
The gamma-aminobutyric acid (GABA) receptor bears sites of action for insecticides. To discover GABA receptor-directed insecticides in natural products, fungal culture extracts were screened for their ability to inhibit specific binding of the radiolabeled noncompetitive antagonist [3H]1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane to housefly head membranes. The screening efforts led to the isolation of two alkaloids from Aspergillus terreus: PF1198A (alantrypinone) and PF1198B (serantrypinone), which had IC50 values of 0.34 and 2.1 microM, respectively, in this assay. These compounds were ca. 47-61-fold selective for housefly vs rat GABA receptors. Both compounds showed insecticidal activity against Myzus persicae in the range of 100-500 ppm. Binding assay-guided screening should provide significant opportunities for the identification of novel and selective insecticides.