Petar Todorov

Recent synthesis of aminophosphonic acids as potential biological importance

Aminophosphonic acids are an important group of medicinal compounds, and their synthesis has been a focus of considerable attention in synthetic organic chemistry as well as medicinal chemistry. Although the phosphonic and carboxylic acid groups differ considerably with respect to shape, size, and acidity, α-aminophosphonic acids are considered to be structural analogues of the corresponding amino acids and the transition state mimics peptide hydrolysis. This review summarizes recent developments in the synthesis, characterization and biological activity of α-aminophosphonic acid and N-analogues. An account of both uses will be presented, emphasizing one of the potential future developments, and some implications in medicinal chemistry are also disclosed. In addition, a brief account on the characterization of N-(phosphonomethyl) glycine derivatives will be presented.

Synthesis and biological activity of novel small peptides with aminophosphonates moiety as NOP receptor ligands

The aim of the present study was the synthesis and the biological screening of new analogs of Ac-RYYRWK-NH2, modified at the N-terminal with 1-[(methoxyphosphono)methylamino]cycloalkanecarboxylic acids. The four newly synthesized ligands for the nociceptin/orphanin FQ (N/OFQ) receptor (NOP) have been prepared by solid-phase peptide synthesis—Fmoc-strategy. These compounds were tested for agonistic activity in vitro on electrically stimulated smooth-muscle preparations isolated from vas deferens of Wistar rats. Our data showed that substitution of Arg at position 1 with aminophosphonates moiety decreased significantly the affinity of ligands to the NOP receptor. Furthermore, the enlargement of the cycle (with 5–8 carbon atoms) additionally diminished both the activity and the selectivity for NOP-receptor.

Structure, conformation and hydrogen bonding of two amino-cycloalkanespiro-5-hydantoins

The crystal structures of 3-amino-cycloheptanespiro-4′-imidazolidine-2′,5′-dione (I) {systematic name: 3-amino-1,3-diazaspiro[4.6] undecane-2,4-dione} and 3-amino-cyclooctanespiro-4′-imidazolidine-2′,5′-dione (II) {systematic name: 3-amino-1,3-diazaspiro[4.7] dodecane-2,4-dione}, have been determined. In both compounds the polar hydantoin groups cause molecules to aggregate via N-H...O and N-H...N interactions, forming a layer structure, in which the cycloalkane rings project outwards from the central, more polar, region. The observed molecular structure is compared with that calculated by density functional theory methods.

Synthesis and changes in affinity for NOP and opioid receptors of novel hexapeptides containing β2-tryptophan analogues

We report the synthesis and the biological activity of new analogues of Ac-RFMWMK-NH2 and Ac-RYYRWK-NH2, modified in position 4 and 5, respectively, with incorporation of newly synthesized β(2)-tryptophan analogues. Trp was substituted by the (S)-2-(1-methyl-1H-indol-3-yl)propionic residue or by (S)-2-(5-methoxy-1H-indol-3-yl)propionic residue. The biological activity (pEC50 and Emax) of these compounds was tested on electrically stimulated preparations of rat vas deferens. The 5-methoxy β-tryptophan group reverses the affinity of the compounds.

Synthesis and Characterization of Novel Cycloalkanespiro-5-Hydantoin Phosphonic Acids

A series of new cycloalkanespiro-5-hydantoin phosphonic acids have been synthesized and characterized. The mixture of [(2,4-dioxo-1,3-diazaspiro-alkane-3-yl)-methyl]phosphonic acids and [(2,4-dioxo-1,3-diazaspiro-alkane-1,3-diyl)dimethyl]diphospho-nic acids was obtained from cycloalkanespiro-5-hydantoins, formaldehyde, and phosphorus trichloride in a molar ratio of 1:2:2, by a procedure modified by us. Their structures were proved by means of IR, 1H, 13C{1H} and 31P NMR spectroscopy.

Synthesis and analgesic effects of novel β2-tryptophan hexapeptide analogs

Aiming to develop more potent analgesic substances a new series of hexapeptides containing β2-tryptophan analogues was synthesized. The Trp in position 4 and 5, respectively in Ac-Arg-Phe-Met-Trp-Met-Lys-NH2 (opioid receptor antagonist) and Ac-Arg-Tyr-Tyr-Arg-Trp-Lys-NH2 (highly potent and selective NOP-receptor agonist) was substituted by the (S)-2-(1-methyl-1H-indol-3-yl)propionic residue or the (S)-2-(5-methoxy-1H-indol-3-yl)propionic residue. The analgesic effect of the four newly synthesized compounds has been evaluated in male Wistar rats by PP- and HP tests and compared to the native templates. Further estimation of the mechanisms of action of each compound was achieved using specific antagonists—naloxone for opioid and JTC801 for the NOP receptor. Replacement of Trp with β2-tryptophan analogues in 4th position (Ac-Arg-Phe-Met-Trp-Met-Lys-NH2) led to increased and longer lasting analgesic effect. The results obtained permit us to assume that both opioid and NOP receptors take part in the newly synthesized compounds analgesic effects.

[(4,4-Dimethyl-2-oxo-1,3-oxazolidin-3-yl)methyl]phosphonic acid.

The title compound, C6H12NO5P, was synthesized as an intermediate phase in a search for new N-(phosphonomethyl)glycine derivatives. The molecules are held together by O-H...O hydrogen bonds, forming chains along the b axis in the crystal structure. The observed molecular structure is compared with that calculated by the density functional theory method.

Synthesis and biological activity of new series of N-modified analogues of the N/OFQ(1–13)NH2 with aminophosphonate moiety

New series of N-modified analogues of the N/OFQ(1–13)NH2 with aminophosphonate moiety have been synthesized and investigated for biological activity. These peptides were prepared by solid-phase peptide synthesis—Fmoc-strategy. The N/OFQ(1–13)NH2 analogues were tested for agonistic activity in vitro on electrically stimulated rat vas deferens smooth-muscle preparations isolated from Wistar albino rats. Our study has shown that the selectivity of the peptides containing 1-[(methoxyphosphono)methylamino]cycloalkanecarboxylic acids to the N-side of Phe is not changed—they remain selective agonists of NOP receptors. The derivative with the largest ring (NOC-6) demonstrated efficacy similar to that of N/OFQ(1–13)NH2, but in a 10-fold higher concentration. The agonistic activity of newly synthesized N-modified analogues of N/OFQ(1–13)NH2 with aminophosphonate moiety was investigated for the first time.

A Study of the Reaction of Phosphorus Trichloride with Paraformaldehyde in the Presence of Carboxylic Acids

Abstract We investigated the mechanism of the reaction of paraformaldehyde with phosphorus trichloride in the presence of carboxylic acids (acetic, propanoic, and formic). Our results revealed that bisphosphonic acids were obtained without the use of water. The structures of the reaction products were studied by 1D and 2D homonuclear and heteronuclear 1H-, 13C-, 31P- NMR spectroscopy. [Supplementary materials are available for this article. Go to the publishers online edition of Phosphorus, Sulfer, and Silicon and the Related Elements for the following free supplemental files: Additional tables.] GRAPHICAL ABSTRACT

Synthesis, characterization and nociceptive screening of new VV-hemorphin-5 analogues

In the present study, some new analogues of VV-hemorphin-5, modified at position 1 and 7 by the non-proteinogenic and/or natural amino acids followed the structures Xxx-Val-Val-Tyr-Pro-Trp-Thr-Gln-NH2 and Val-Val-Tyr-Pro-Trp-Thr-Yyy-NH2, where Xxx is Ile or Aib and Yyy is Lys/Orn/Dap/Dab were synthesized to investigate their potential antinociceptive activities. We report also the redox potentials and the acid/base properties as pKa values of these peptide analogues which were compared toward electrochemical behaviour of tryptophan containing peptides. All analogues showed a short lasting initial antinociceptive effect, however H2 hemorphin analogue is characterized with prolong and strong antinociceptive effect, while the other peptide analogues exerted more variable effects on the visceral nociception depending on the dose or time after the intracerebral injection.