Isothiocyanates as Tubulin Polymerization Inhibitors-Synthesis and Structure-Activity Relationship Studies.

Among the various substances that interfere with the microtubule formation process, isothiocyanates (ITCs) are the group of compounds for which the binding mode and mechanism of action have not yet been explained. To better understand the structure-activity relationship of tubulin-isothiocyanate interactions, we designed and synthesized a series of sixteen known and novel, structurally diverse ITCs, including amino acid ester-derived isothiocyanates, bis-isothiocyanates, analogs of benzyl isothiocyanate, and phosphorus analogs of sulforaphane. All synthesized compounds and selected natural isothiocyanates (BITC, PEITC, AITC, and SFN) were tested in vitro to evaluate their antiproliferative activity, tubulin polymerization inhibition potential, and influence on cell cycle progression.

Boronic acid-based arginase inhibitors in cancer immunotherapy.

Arginase is an enzyme that converts l-arginine to l-ornithine and urea in the urea cycle. There are two isoforms of arginase in mammals: ARG-1 and ARG-2. l-Arginine level changes occur in patients with various types of affliction.

New diaryl ω-(isothiocyanato)alkylphosphonates and their mercapturic acids as potential antibacterial agents.

Thirty-four novel, diaryl ω-(isothiocyanato)alkylphosphonates with chlorine atom and methoxy, dimethoxy, methylsulfanyl, or methoxycarbonyl groups at ortho, meta, or para positions of the phenyl ring, and with an unbranched alkyl chain (n = 2-6) were designed and synthesized in a one-pot reaction in 11-76% yields. All isothiocyanates thus generated were evaluated for the first time for antibacterial activity on Pseudomonas aeruginosa and Staphylococcus aureus bacterial strains, and had satisfactory antibacterial activity in most cases. The highest activity, similar to that of reference gentamicin activity against S.

Phosphorus-containing isothiocyanate-derived mercapturic acids as a useful alternative for parental isothiocyanates in experimental oncology.

A series of phosphonates, phosphinates and phosphine oxides isothiocyanate-derived mercapturic acids were synthesized. A temperature dependence dynamic proton decoupled P NMR studies indicated that in most cases the compounds were obtained as a mixture of rotamers. Moreover, biologically relevant reversibility of mercapturic acids synthesis from the parental isothiocyanates was confirmed.

Design, Synthesis, and Evaluation of ω-(Isothiocyanato)alkylphosphinates and Phosphine Oxides as Antiproliferative Agents.

A series of 21 novel, structurally diverse ω-(isothiocyanato)alkylphosphinates and phosphine oxides (ITCs) were designed and synthesized in moderate to good yields. The synthesized compounds were evaluated for in vitro antiproliferative activity using LoVo and LoVo/DX cancer cell lines. The biological activity of the synthesized compounds was higher than that of natural isothiocyanates such as benzyl isothiocyanate or sulforaphane.

Novel phosphonate analogs of sulforaphane: Synthesis, in vitro and in vivo anticancer activity.

A library of over forty, novel, structurally diverse phosphonate analogs of sulforaphane (P-ITCs) were designed, synthesized and fully characterized. All compounds were evaluated for antiproliferative activity in vitro on Lovo and LoVo/DX colon cancer cell lines. All compounds exhibited high antiproliferative activity, comparable or higher to the activity of naturally occurring benzyl isothiocyanate and sulforaphane.

Friedel-Crafts-type reaction of pyrene with diethyl 1-(isothiocyanato)alkylphosphonates. Efficient synthesis of highly fluorescent diethyl 1-(pyrene-1-carboxamido)alkylphosphonates and 1-(pyrene-1-carboxamido)methylphosphonic acid.

Friedel-Crafts-type reaction of pyrene with diethyl 1-(isothiocyanato)alkylphosphonates promoted by trifluoromethanosulfonic acid afforded diethyl 1-(pyrene-1-carbothioamido)alkylphosphonates in 83-94% yield. These compounds were transformed, in 87-94% yield, into the corresponding diethyl 1-(pyrene-1-carboxamido)alkylphosphonates by treatment with Oxone(®). 1-(Pyrene-1-carboxamido)methylphosphonic acid was obtained in a 87% yield by treating the corresponding diethyl phosphonate with Me3Si-Br in methanol.

Synthesis and biological activity of diisothiocyanate-derived mercapturic acids.

This Letter deals with new non-natural diisothiocyanates, their mercapturic acid derivatives-conjugated with N-acetylcysteine as well as their antiproliferative activity towards human colon cancer cell lines and their inhibitory potency towards histone deacetylase activity. The activity of analysed isothiocyanates is not significantly different than their N-acetylcysteine conjugates. In comparison to simple mono-isothiocyanate analogues, aliphatic diisothiocyanates and their conjugates are much more active than the simple presence of two isothiocyanate functionalities could indicate.

Differentiation of diastereoisomers of protected 1,2-diaminoalkylphosphonic acids by EI mass spectrometry and density functional theory.

Electron ionization mass spectrometry and density functional theory (DFT) calculations have been used to study the fragmentation of diastereoisomers of protected 1,2-diaminoalkylphosphonic acids. The loss of a diethoxyphosphoryl group and the elimination of diethyl phosphonate were found to be competitive fragmentation processes, which can be used to differentiate both stereoisomers. Selective deuterated analogs and product- and precursor-ion mass spectra allowed the elucidation of the fragmentation mechanisms.

Synthesis and antiproliferative activity of novel α- and β-dialkoxyphosphoryl isothiocyanates.

A series of 15 mostly new dialkoxyphosphoryl alkyl and aralkyl isothiocyanates were synthesized using two alternative strategies, and their in vitro antiproliferative activity against several cancer cell lines (including drug resistant) is here demonstrated. The IC(50) values measured for the new compounds are within the range of 6.3-21.

Stereochemical effects in fragmentation of diastereoisomers of protected diethyl 1,2-diamino-alkylphosphonates.

Diastereoisomers of diethyl 5-substituted (2-thioxo-imidazolidin-4-yl)phosphonates, which can be regarded as protected diethyl 1,2-diaminoalkylphosphonates, have been analyzed by electron ionization mass spectrometry. Significant differences in the fragmentation of cis- and trans-diastereoisomers were found. The stereospecificity of the elimination of diethyl phosphonate and the loss of the diethoxyphosphoryl group were studied using specific labeled compounds and collision-induced dissociation.

N-carbamate protected alpha-amidoalkyl-p-tolylsulfones: convenient substrates in the aza-Morita-Baylis-Hillman reaction.

An efficient and practical one-pot approach to aza-Morita-Baylis-Hillman adducts has been developed. The reaction occurs between N-Boc or N-Cbz imines, generated in situ from stable and easy to handle N-Boc or N-Cbz protected alpha-amidoalkyl-p-tolylsulfones, and electron-deficient alkenes in the presence of DABCO. The presented procedure eliminates the use of the relatively unstable N-carbamate imines prior to the coupling reaction.

The assignment of the absolute configuration of diethyl hydroxy- and aminophosphonates by 1H and 31P NMR using naproxen as a reliable chiral derivatizing agent.

The assignment of the absolute configuration of hydroxy- and aminophosphonates by their double derivatization with commercially available naproxen is presented. The correlation between the spatial arrangement around the stereogenic carbon center and the signs of the DeltadeltaRS allows determination of the absolute configuration of hydroxy- and aminophosphonates by simple comparison of the 1H and 31P NMR spectra of the (R)- and (S)-naproxen ester or amide derivatives. Extensive conformational analysis (theoretical calculations, low-temperature experiments) supported by the NMR studies of structurally diverse naproxen esters and amides of hydroxy- and aminophosphonates proved that a simplified model can be successfully used.