Long chain diamines inhibit growth of C6 glioma cells according to their hydrophobicity. An in vitro and molecular modeling study

A series of diamines with the general structure NH2(CH2)xNH2, x=2-12, was tested for their potential effects on cell proliferation of cultured rat C6 glioma cells in comparison to natural polyamines. Long chain diamines reduced cell number after 48 h in culture with a sequence of 1,12-diaminododecane (1,12-DD) >1,10-diaminodecane >1,9-diaminononane. Polyamines (putrescine, spermidine and spermine) as well as diamines up to a CH2-chain length of x=8 were found to be ineffective. The spermine analogue 1,12-DD was the most effective molecule in reducing cell number in an irreversible, dose-dependent manner (EC50=3 microM under serum-free conditions). In further experiments we investigated the mechanisms of action of 1,12-DD. The compound had only a minor effect on cell cycle and did not affect free internal calcium concentration. Under physiological conditions 1,12-DD interacts with triplex DNA but not with duplex DNA. Ornithine decarboxylase activity as well as the concentration of internal polyamines were found to be reduced by 1,12-DD. Polyamine application, however, was not able to reverse the effect of 1,12-DD, indicating a polyamine-independent or non-competitive mechanism of action. 1,12-DD reduced cell number by induction of apoptosis as well as necrosis. In molecular modeling studies it was found that a minimal hydrophobic intersegment of at least 4 A was required to make a diamine an effective drug in respect to cellular growth. A hydrophobic gap of this size fits the minimum requirement expected from molecular modeling to provide space for hydrophobic interactions with parts of proteins like a CH3-group. Our results show that 1,12-DD acts as a potent drug, reducing the number of C6 glioma cells, and suggest that its spatial and hydrophobic properties are responsible for its mechanism of action.     

Transfection efficiencies of PAMAM dendrimers correlate inversely with their hydrophobicity

Dendriplexes were characterized by ethidium bromide intercalation assay and their transfection efficiency was studied using HEK 293 cells and human mesenchymal stem cells. PAMAM G4 showed a higher transfection efficiency than PAMAM G3–G6, G4-OH, G4-25% or G4-50% dendrimers. Substitution of OH groups for the NH₂ surface groups rendered the dendrimer unable to form dendriplexes and to transfect cells. Partial (25%) substitution of CH₃ groups for the NH₂ groups markedly impaired transfection; 50% substitution decreased the ability of PAMAM G4 to transfect threefold. It was concluded that increased hydrophobicity decreased the ability of dendrimers to transfect. PAMAM G4-50% is highly hydrophobic and forms micelles in solution, which can transfect pGFP. The results of ethidium bromide intercalation assays, ANS fluorescence studies and transfection efficiencies of PAMAM dendrimers were correlated. Subsequently, we constructed a neurotrophin-encoding plasmid and studied its delivery to mesenchymal stem cells using PAMAM G4 dendrimer and Lipofectamine 2000. Lipofectamine 2000 was a more effective carrier (18.5%) than PAMAM G4 dendrimer (1.2%).     

Dependence of molecular properties on proteomic family for marketed oral drugs

An association of drugs with their proteomic family reveals that molecular properties of drugs targeting proteases, lipid and peptide G-protein-coupled receptors (GPCRs), and nuclear hormone receptors significantly exceed limits for some properties in the "rule of five", while drugs targeting cytochrome P450s, biogenic amine GPCRs, and transporters have significantly lower values for certain properties. Also, the variation in drug targets appears to be a factor explaining increasing molecular weight over time.     

Structure-activity relationship of mutagenic aromatic and heteroaromatic nitro compounds. Correlation with molecular orbital energies and hydrophobicity

A review of the literature yielded data on over 200 aromatic and heteroaromatic nitro compounds tested for mutagenicity in the Ames test using S. typhimurium TA98. From the data, a quantitative structure-activity relationship (QSAR) has been derived for 188 congeners. The main determinants of mutagenicity are the hydrophobicity (modeled by octanol/water partition coefficients) and the energies of the lowest unoccupied molecular orbitals calculated using the AM1 method. It is also shown that chemicals possessing three or more fused rings possess much greater mutagenic potency than compounds with one or two fused rings. Since the QSAR is based on a very wide range in structural variation, aromatic rings from benzene to coronene are included as well as many different types of heterocycles, it is a significant step toward a predictive toxicology of value in the design of less mutagenic bioactive compounds.     

Inhibition of N-methyl-D-aspartate-induced noradrenaline release by alcohols is related to their hydrophobicity

In rat brain cortex slices, ethanol was three times more potent in inhibiting [3H]noradrenaline ([3H]NA) release evoked by N-methyl-D-aspartate (NMDA) than in inhibiting the release evoked by kainic acid. Methanol, 1-propanol, 1-butanol, 1-pentanol and 1-hexanol shared the inhibitory property of ethanol on NMDA-evoked [3H]NA release. The inhibitory potency of the alcohols, as expressed by their IC50 values, was correlated with their membrane/buffer partition coefficient. It is concluded that the inhibitory effect of the alcohols may be due to a hydrophobic interaction with the NMDA receptor system.     

Effects of molecular mass and hydrophobicity on transport rates through non-specific pathways of the silkworm larva midgut

We previously reported that therapeutic drug effects in the silkworm infection model are largely influenced by midgut permeability. In this report, we describe the effects of drug molecular mass and hydrophobicity on transport through the silkworm larva midgut membrane. Hydrophilic compounds with a molecular mass of greater than 400Da did not permeate the silkworm larva midgut, and the hydrophobicity of similar-sized compounds had positive effects on the transport rate. Furthermore, we compared transport rates through the midgut membrane between cefcapene sodium (CFPN-Na) and cefcapene pivoxil (CFPN-PI), which is a CFPN-Na prodrug. The in vitro transport rate of CFPN-PI was three times faster than that of CFPN-Na. Moreover, when CFPN-PI and CFPN-Na were injected into the living silkworm larva midgut, CFPN-PI appeared rapidly in the haemolymph, whereas CFPN-Na did not. The 50% effective dose (ED50) of CFPN-PI administered via the midgut was one-sixth that of CFPN-Na. These findings suggest that the general features of the non-specific transport route are similar between silkworm larvae and mammals.