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An improved and efficient synthetic route towards piperidino-piperazine based CCR5 antagonists was developed. The new approach was flexible for introducing various substituents in the pharmacophore sites via Grignard reagent addition and reductive amination. l -Amino acids were used as a chiral pool to introduce and then induce the desired stereochemistries, meanwhile rendering the variable substitution. The efficient construction of the piperazino-piperidine nucleus was achieved in a highly convergent manner with a key building block of N1-Boc-4-substituent-4-aminopiperidine, exhibiting significant advantages in terms of concise synthetic route and environmental-friendly reagents over the previously described stepwise synthesis, in which a modified Strecker reaction was involved with highly toxic reagents such as diethylaluminum cyanide.

The Panlong river passes through Kunming City and receives a large quantity of municipal sewage and wastewater from industrial effluent. Along the river, 20 sites were selected to collect water samples to assess the genotoxicity using two Tradescantia assays, the micronucleus (Trad-MCN) and the stamen-hair-mutation (Trad-SHM) assays. The lowest frequencies in the Trad-MCN assay and the Trad-SHM assay are 3.19 MCN/100 tetrads and 1.32 M/1000 stamen hairs, respectively. In the water samples obtained from the Songhua Reservoir, the MCN frequencies and mutation rates are not statistically significantly different from the data found for the negative control (2.49 MCN/100 tetrads and 0.71 M/1000 stamen hairs). Among the other water samples, 19 in Trad-MCN assay and 17 in Trad-SHM assay show significantly higher genotoxicity than the control. The highest genotoxicity was in samples No. 19 for the MCN assay (8.73 MCN/100 cells), over three times higher than the negative control, and in sample No. 11 for the SHM assay (4.30 M/1000), six times higher than the negative control, and were about the same as for the positive control (10.0 mg/l NaN3, 9.28 MCN/100 tetrads and 7.44 SHM/1000 stamen hairs), respectively. The peak frequencies for the Trad-MCN assays were observed in the water samples obtained from the sites that were near industrial and municipal wastewater that ran into the river as effluent. In general, the frequency of MCN and SHM mutations increased where the river passed through Kunming. The Trad-MCN assay seemed more sensitive than that of the Trad-SHM assay in detecting genotoxicity of the river water pollution.

Dianchi Lake covers about a 300 km2 area. Kunming city on the edge of the lake is surrounded by industrial establishments. Farm land surrounds the remaining areas of the lake. The lake water is polluted by the Kunming city municipal sewage from 3 million inhabitants, the industrial effluent and farm runoff. Water samples were collected from 12 sites along the shore of the lake during the dry (May) and rainy (August) seasons for genotoxicity testing with the Vicia micronucleus assay during the year 1995. Genotoxicity in terms of micronuclei (MCN) frequencies in the root tip cells of Vicia showed a consistent elevated frequency of MCN over the control sample at the 0.05-0.01 levels of significance in both seasons. The MCN frequencies of sites A (Daguanhe), B (Gaoqiao) and C (Xiyuan) were 3.5-4 times as high as the control values (5.25/1000 cells) in the dry season. In the rainy season, the MCN frequencies of water samples from most of the 12 sites were relatively lower than those of the dry season except sites J (Haikou), and K (Kunyang). The average MCN frequency of the dry season samples was 14.97 per 1000 cells and that of the rainy season samples was 12.24 per 1000 cells while the average control value was around 5.00/1000 cells.