Anticancer potency of small linear and cyclic tetrapeptides and pharmacokinetic investigations of peptide binding to human serum albumin

We have in the present study explored the anticancer activity against human Burkitt's lymphoma cells (Ramos) of a series of small linear and cyclic tetrapeptides containing a β^2,2‐amino acid with either two 2‐naphthyl‐methylene or two para‐CF₃‐benzyl side chains, along with their interaction with the main plasma protein human serum albumin (HSA). The cyclic and more amphipathic tetrapeptides revealed a notably higher anticancer potency against Ramos cells [50% inhibitory concentration (IC₅₀) 11–70 μM] compared to the linear tetrapeptide counterparts (IC₅₀ 18.7 to >413 μM). The most potent cyclic tetrapeptide c3 had a 16.5‐fold preference for Ramos cells compared to human red blood cells, whereas the cyclic tetrapeptide c1 both showed low hemolytic activity and displayed the overall highest (2.9‐fold) preference for Ramos cells (IC₅₀ 23 μM) compared to healthy human lung fibroblast cells (MRC‐5). Investigating the interaction of selected tetrapeptides and recently reported hexapeptides with HSA revealed that the peptides bind to drug site II of HSA in the 22–28 μM range, disregarding size and overall structure. NMR and in silico molecular docking experiments identified the lipophilic residues as responsible for the interaction, but in vitro studies showed that the anticancer potency of the peptides varied in the presence of HSA and that c3 remained the most potent peptide. Based on our findings, we call for implementing serum albumin binding in development of anticancer peptides, as it may have implications for future administration and systemic distribution of peptide‐based cancer drugs. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.     

13C-n.m.r. studies of monomeric composition and sequence in alginate

High-resolution, ¹³C-n.m.r. spectra of slightly depolymerised alginates have been interpreted. The sequence of monomer units, l-guluronate (G) and d-mannuronate (M), markedly influenced the chemical shifts. At 50 MHz, some of the individual carbon resonances of both units were resolved into four lines, in evident dependence upon the identities of the units immediately preceding and following them in the chains. The relative intensifies of the signals permitted rapid computation of (1) monomeric composition (M/G ratio), (2) monomeric sequence in terms of a complete set of four diad and eight triad frequencies, and (3) the composition (M/G ratio) of end units and of the units adjacent to M-residues at the non-reducing end. The diad frequencies indicated that alginate was a block co-polymer containing number-average, co-monomer block-lengths of ～2?8. The triad frequencies indicated average lengths of ～4?8 for blocks containing two or more units, these being somewhat longer for G- than for M-blocks. Regions of the chains having a strictly alternating sequence of M- and G-residues were short. The relative occurrence of G-centred triads deviated significantly from those predicted by first-order Markovian statistics.     

Acute unstable depressive syndrome (AUDS) is associated more frequently with epilepsy than major depression

Background  

Depressive disorders are frequent in epilepsy and associated with reduced seizure control. Almost 50% of interictal depressive disorders have to be classified as atypical depressions according to DSM-4 criteria. Research has mainly focused on depressive symptoms in defined populations with epilepsy (e.g., patients admitted to tertiary epilepsy centers). We have chosen the opposite approach. We hypothesized that it is possible to define by clinical means a subgroup of psychiatric patients with higher than expected prevalence of epilepsy and seizures. We hypothesized further that these patients present with an Acute Unstable Depressive Syndrome (AUDS) that does not meet DSM-IV criteria of a Major Depressive Episode (MDE). In a previous publication we have documented that AUDS patients indeed have more often a history of epileptic seizures and abnormal EEG recordings than MDE patients (Vaaler et al. 2009). This study aimed to further classify the differences of depressive symptoms at admittance and follow-up of patients with AUDS and MDE.