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| Author(s): |
Mauro Vicentini Correia
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) |
| Defense date: | 2015-03-23 |
| Examining board members: |
Massuo Jorge Kato;
Marcelo José Pena Ferreira;
João Henrique Ghilardi Lago;
Gustavo Henrique Goulart Trossini;
Claudio Di Vitta
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| Advisor: | Massuo Jorge Kato |
| Abstract | |
The natural 2-acyl-cyclohexane-1,3-diones have quite restricted occurrence, being reported from only two plant genera (Peperomia, Philodendron and Virola) and from two insects orders, Lepidoptera and Hymenoptera, in which cytotoxic and kairomonal activities were reported. The 77 polyketides of 2-acyl-cyclohexane-1,3-diones type synthesized (36 novel) were tested for cytotoxic activity against three leukemia cells lines (K562, Nalm6 and Raji), and as inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD) enzyme, an important target for herbicidal activity. The analysis of structure and activity relationship (SAR) revealed the main structural requirements for the activities studied to predict the cytotoxic activity and inhibition of HPPD enzyme of 2-acyl-cyclohexane-1,3-diones. Two statistical methods (Linear Multiple Regression (MLR) and Discriminant Analysis using partial least squares (PLS-DA)) were used for the construction of quantitative and qualitative prediction models. In the multiple linear regression model (MLR), quantitative models explained more than 80% of the variance of the activity, with hit rates higher than 85% in the external validation. In the classification models obtained from the PLS-DA method, the compounds were divided as active or inactive, with hit rates above 80% in all the models generated. The most important characteristics for the inhibition of the activity of the enzyme HPPD were the size of the side chain and the presence of the enolic group (4a, 5a, 5d e 5e). For the cytotoxic activity in the aliphatic series, the side chain with 9-11 carbons (4e, 5a e 6a) showed higher inhibition indices, while for aromatic series conjugation with a double bond (8a, 11c e 14a) and withdrawing groups in the aromatic ring (16a, 17c e 19a) presented higher activity. (AU) | |