Effect of acylated amino acids and acylated amino acid analogs on microbial antitumor screen.

A series of N-acetyl,-N-propionyl, and N-chloroacetyl derivatives of amino acids and amino acid analogs was tested for growth-inhibitory activity using a Lactobacillus casei system as a prescreen for possible antitumor activity. While none of the acetyl or propionyl derivatives of these amino acids and amino acid analogs caused any remarkable inhibition, certain chloroacetyl derivatives exhibited significant activity. The chloroacetyl derivatives, especially those of essential amino acids and of analogs of essential amino acids, showed modest, but pharmacologically significant, inhibition; those of nonessential amino acids exhibited no activity. When two such inhibitory acyl derivatives were combined in a single assay, the extent of inhibition was neither additive nor synergistic but was that of the more active of the two test components.     

N-Benzoyl derivatives of amino acids and amino acid analogs as growth inhibitors in microbial antitumor screen.

Twenty-seven N-benzoyl derivatives of amino acids and amino acid analogs were prepared and tested for growth-inhibitory activity in a microbial antitumor screen. Of these, 19 showed some inhibitory capacity, from a modest 13% to a potent 96% at 1 mg/ml. The activities of the "modest" inhibitors were comparable to those of most inhibitory chloracetyl and trifluoroacetyl derivatives reported earlier. The intermediate inhibitors were as active as N-chloroacetyl-beta-hydroxy-D-norleucine isomer B, the most active acyl derivative noted previously. The most active compounds in this study were N-benzoyl-p-chloro-DL-phenylalanine and N-benzoyl-m-fluoro-DL-phenylalanine, which inhibited the test organism almost completely under the assay conditions.     

Synthesis and antitumor evaluation of some nitrosourea and nitrogen mustard amino acid derivatives

A series of (2-chloroethyl)nitrosourea and nitrogen mustard amino acid derivatives have been synthesized for antitumor evaluation. Reaction of an appropriate N-protected amino acid with 2-chloroethylamine followed by removal of the N-protecting group and condensation with an active (2-chloroethyl)nitrosocarbamate yielded N-[(2-chloroethyl)nitrosocarbamoyl]amino acid (2-chloroethyl)amides. Antitumor evaluation was performed against leukemia L1210, in vivo, in mice. These derivatives exhibited very interesting activities, particularly the sarcosine and gamma-aminobutyric acid derivatives.     

Influence of amino acids on okadaic acid production.

Okadaic acid (OA) (1)) was the first example of a group of polyether toxins known to be produced by marine microalgae, which are responsible for the natural phenomena known as Diarrhetic Shellfish Poisoning (DSP) red tides. It is also a highly selective inhibitor of protein phosphatases type 1 (PP1) and 2A (PP2A), as well as being a potent tumour promoter. For these reasons, OA is an extremely useful tool for studying cellular processes and an important standard for polluted shellfish control. In this paper, we report on a double objective: to improve the production of toxins and verify the apparent participation of amino acids in the formation of these polyethers by monitoring their influence on the promotion of growth, total cell yield and increased in toxicity in Prorocentrum lima of the PL2V strain in batch cultures, in a modified K medium.     

Antibacterial halogenoacetyl derivatives of amino acids and simple peptides.

The vital role of D-alanine and L-lysine in the peptidoglycan crosslinking process in the bacterial cell wall prompted preparation of various small peptides incorporating these amino acids. N-Iodoacetyl or -bromoacetyl derivatives of the peptides were then prepared in the hope that they would serve as active-site-directed irreversible inhibitors of cell wall transpeptidases. Certain of the halogenoacetyl dipeptide esters, but not the corresponding free acids, showed slight antistaphylococcal activity. Subsequent structural variation showed that inclusion of C-alanine or L-lysine was not necessary, since antibacterial activity was at least as good when the dipeptide unite was replaced by glycylglycine or by an omega-aminoalkanoic acid. It was concluded that the observed antibacterial activity was probably not due to specific inhibition of a cell wall transpeptidase.     

Potential antitumor agents: synthesis and biological properties of aliphatic amino acid 9-hydroxyellipticinium derivatives

Aliphatic amino acids glycine, alanine, valine, and leucine were conjugated to the antitumor drug N2-methyl-9-hydroxyellipticinium (NMHE) through a peroxidase-catalyzed oxidation reaction. NMR studies of the adducts so obtained have indicated (i) that the amino acids were linked to NMHE between the nitrogen of their primary amine and the C-10 position of the ellipticine ring and (ii) that a double bond was present between the nitrogen and the alpha-carbon of the amino acid moiety. All amino acid-NMHE adducts exhibit a higher lipophilic property than the parent compound (NMHE) directly correlated with the length of the aliphatic chain of the amino acids. The adducts interact with DNA through an intercalating process with apparent binding constant ranging from 2 X 10(5) to 5 X 10(5) M-1 at pH 7.40. The presence of the amino acid moiety linked to NMHE results (i) in a slight decrease of the cytotoxicity on L1210 cells in vitro (ID50 ranged from 0.20 to 0.50 microM) as compared to NMHE (ID50 = 0.05 microM), (ii) in a decrease of the antitumor efficiency in vivo against L1210 leukemia for leucine-NMHE and valine-NMHE (ILS at LD0/2 = 35% and 31%, respectively), (iii) in a suppression of the antitumor activity for alanine-NMHE and glycine-NMHE (ILS less than 25%), (iv) in a strong increase in the bacteriostatic activity on the quaternary ammonium sensitive Escherichia coli BL101 strain and on Salmonella typhimurium TA98 strain. The bacteriostatic effect is directly correlated with the lipophilic property of the drugs. These findings are discussed in terms of a structure-activity relationship.     

Capillary electrophoretic separation of enantiomers of amino acids and amino acid derivatives using crown ether and cyclodextrin

The capillary zone electrophoresis using (+)-18-crown-6-tetracarbonic acid as a chiral selector was a suitable method for the enantiomeric separation of racemates of amino acids and of some amino acid derivatives (esters, dipeptides). The influence of the chemical structure of the compounds on the separation was investigated. After optimization of the separation conditions, baseline separations were obtained for most racemates. The addition of acetonitrile and TBAB yielded an improvement of the separation. Improved selectivity was further observed by the application of a cyclodextrin, HP-beta-CD, in combination with the crown ether.     

Deaza analogs of folic acid as antitumor agents

Derivatives of the vitamin folic acid function in the body for the synthesis of thymidylate, purines and amino acids and are necessary for normal metabolism and growth. Methotrexate (MTX), an inhibitor of dihydrofolate reductase (DHFR) is the outstanding example of an antitumor antifolate. MTX is clinically useful in the treatment of childhood leukemia, choriocarcinoma and psoriasis, where it corrects abnormal growth, and in rheumatoid arthritis and other autoimmune diseases where it corrects abnormal immune function. Since 1949, when the chemical synthesis of MTX was reported by workers at the Lederle Laboratories of the American Cyanamid Company, much has been learned about the basis of antifolate cytotoxicity and selectivity. This review will focus on deaza antifolates which are: 1). presently under clinical development and 2). less developed compounds which represent novel approaches. Compounds will be grouped according to their enzyme targets; DHFR, thymidylate synthase (TS) and glycinamide ribonucleotide formyltransferase (GARFT). In addition to inhibition of target enzymes, antifolate membrane transport into cells and conversion to poly-L-gamma-glutamate forms are important considerations in drug design along with the reverse processes, cellular hydrolysis of antifolate poly-L-gamma-glutamates to monoglutamates and the extrusion of the monoglutamates through the cell membrane. These processes can be modulated by competition with folates.     

Synthesis and antitumor activity of amino derivatives of pyridine-2-carboxaldehyde thiosemicarbazone.

Various substituted pyridine-2-carboxaldehyde thiosemicarbazones (12 compounds) have been synthesized and evaluated for antineoplastic activity in mice bearing the L1210 leukemia. Oxidation of 3-nitro-2-picoline,5-nitro-2-picoline,3-nitro-2,4-lutidine, and 5-nitro-2,4-lutidine with selenium dioxide was employed to generate the corresponding pyridine-2-carboxaldehydes, which were then converted to cyclic ethylene acetals and subsequently reduced to amino and hydroxyamino derivatives by catalytic hydrogenation. Condensation of nitro aldehydes and acetals with thiosemicarbazide afforded the respective thiosemicarbazones. Acetylation of the amino acetals and alkylsulfonation of the 5-amino acetal, followed by condensation with thiosemicarbazide was employed to yield amide thiosemicarbazones. The most active compounds synthesized were 3-aminopyridine-2-carboxaldehyde thiosemicarbazone and 3-amino-4-methylpyridine-2-carboxaldehyde thiosemicarbazone which produced against the L1210 leukemia, % T/C values of 246 and 255, and 40% 60-day long-term survivors at two daily doses of 40 mg/kg and 10 mg/kg, respectively, for six consecutive days.