1. Synthesis of cis-4-guanidino-L-proline and 1-carbamimidoyl-L-proline derivatives as influenza neuraminidase inhibitors
Yuanchao Xie • Dongqing Xu • Junhua Wang • Weidong Xiao • Wenfang Xu. Med Chem Res (2015) 24:1013–1017
Peramivir (Fig. 1) consisting of a cyclopentane backbone with a positively charged guanidinyl group and a carboxylic group is one potent influenza NA inhibitor. It has been approved for the treatment of influenza infection recently. Previously, we synthesized and crystallized cis-4-azido-L-proline (compound 1, Scheme 1) methyl ester from L-hyp. In the light of the structure of peramivir, the present work continued to synthesize some cis-4-guanidino-L-proline derivatives and 1-carbamimidoyl-L-proline derivatives by simple procedures. The preliminary influenza NA inhibition assay indicated that some compounds present mild inhibitory activity against influenza NA and could be further modified.
2. Enhancement of anthraquinone production in Morinda citrifolia cell suspension cultures after stimulation of the proline cycle with two proline analogs
Carla V. Quevedo • Marıa Perassolo • Ana M. Giulietti • Julian Rodrıguez Talou. Biotechnol Lett (2012) 34:571–575
If the proline cycle is coupled with the first steps of the pentose phosphate pathway (PPP) (Shetty 2004) then the reduction of glutamate to formproline renders two NADPH which could be used as cofactors of the first enzymes in the PPP. Thus, by stimulating the proline cycle, it should be possible to increase the carbon flux through the PPP and towards the shikimate pathway, since its precursor, erythrose 4-phosphate, is the end-product of the PPP. Proline analogs have been used to enhance the proline cycle because, since they are competitive inhibitors of proline dehydrogenase (PDH), proline accumulates to overcome this inhibition (Shetty et al. 2003; Yang and Shetty 1998).
3. Stimulation of the proline cycle and anthraquinone accumulation in Rubia tinctorum cell suspension cultures in the presence of glutamate and two proline analogs
Marıa Perassolo • Carla Veronica Quevedo • Ana Marı ´a Giulietti • Julian Rodrıguez Talou. Plant Cell Tiss Organ Cult (2011) 106:153–159
It has been proposed that the proline cycle could affect the PPP, since its synthesis from glutamate generates two molecules of NADP?, which act as cofactors of the first two enzymes in the PPP, the glucose-6-phosphate dehydrogenase (G6PDH) and the 6-phosphogluconate dehydrogenase (Shetty and Wahlqvist 2004). Stimulating the proline cycle of biosynthesis and degradation could induce the PPP and generate an excess of erythrose-4-phosphate, therefore, driving the carbon flux toward the shikimate pathway (Shetty and Wahlqvist 2004). Induction of the proline cycle could be achieved by the addition of glutamate or proline to the culture media. In a previous work, it was reported that the addition of 0.25 mM of proline to R. tinctorum cell suspension cultures increased AQs accumulation by up to 50% after 7 days of treatment, although it could not be proved that this finding was a consequence of the stimulation of the proline cycle (Perassolo et al. 2007). The addition of proline analogs is another way to stimulate the proline cycle, since they act as competitive inhibitors of proline dehydrogenase (PDH). It was previously shown that 200 lM of azetidine-2-carboxylic acid (A2C) enhanced total phenolics, proline, and G6PDH activity in Vicia faba (Shetty et al. 2003). Thiazolidine-4-carboxylic acid (T4C), another proline analog, was found to affect proline metabolism in Hordeum vulgare, exhibiting different effects on turgid and wilted leaves (Elthon and Stewart 1984).
