(S)-2-(4-Chlorobenzoyl)-1,2,3,4-tetrahydrobenzo[e]pyrazino[1,2-a][1,4]diazepine-6,12(11H,12aH)-dione—Synthesis and Crystallographic Studies

Abstract

(S)-2-(4-Chlorobenzoyl)-1,2,3,4-tetrahydrobenzo[e]pyrazino[1,2-a][1,4]diazepine-6,12(11H, 12aH)-dione was obtained in a three-step, one-pot synthesis, starting from optically pure (S)-2-piperazine carboxylic acid dihydrochloride. Selective acylation of the β-nitrogen atom followed by condensation with isatoic anhydride and cyclization with HATU/DIPEA to a seven-member benzodiazepine ring, led to the tricyclic benzodiazepine derivative. Crystallographic studies and initial biological screening were performed for the title compound.

Design and in Vitro Characterization of Tricyclic Benzodiazepine Derivatives as Potent and Selective Antileukemic Agents

“…Compounds 16 – 22 were synthesized using our previously‐reported three‐step procedure involving: 1) selective acylation of the optically active ( S )‐piperazine‐2‐carboxylic acid with biphenyl‐4‐carbonyl or biphenyl‐3‐carbonyl chlorides, 2) a second acylation with substituted isatoic anhydride, then, 3) the formation of a 7‐membered diazepine ring using a peptide coupling reagent HATU in the presence of DIPEA [7,8] . We previously obtained the crystallographic structures of compounds 6 , [7] 2 and 5 , [8] which exhibited no ( 2 , 6 ) or moderate ( 5 ) biological activity. To better understand the relationship between its biological effects and for designing new, more effective ligands, we attempted to undertake crystallographic studies of all new derivatives.…”

“…Available antileukemic drugs usually cause strong adverse events and side effects, [4–6] necessitating the design of more selective and efficient anticancer agents. Recently, we identified a small library of tricyclic benzodiazepine derivatives 1 – 15 ( Figure 1 ) that exhibit a relatively selective cytotoxicity against the MV‐4‐11 (biphenotypic B myelomonocytic leukemia) and LoVo (colorectal adenocarcinoma) cell lines [7,8] . In particular, the lead compound 9 exhibited significant cytotoxic effect on the leukemic cell lines MV‐4‐11 (IC 50 ±SD=17.5±2.4 μM), moderate cytotoxic effect on the LoVo cell lines (IC 50 =55.0±16.2 μM) and weak cytotoxic effect on the reference cell lines Balb/3T3 (fibroblasts from mouse embryo, IC 50 =79.6±5.1 μM).…”

“…With the above in mind, this study aimed to understand the influence of tricyclic benzodiazepines on the activity of ATX and further correlate this with their cytotoxicity. To achieve this, we complemented our existing library of compounds 1 – 15 , [7,8] with 7 new compounds ( 16 – 22 , Figure 1). We then assessed the effect of compounds 1 – 22 on the hydrolytic activity of recombinant human ATX, determined the ligand–protein inhibition constants for the most active compounds, solved crystallographic structures of three derivatives ( 11 , 17 and 19 ), and correlated the structure–activity relationship (SAR) of compounds 16 – 22 with their selective cytotoxicity toward the leukemic MV‐4‐11 and CCRF‐CEM cell lines.…”

5-Methyl-3,8-di-(2-amino-4-bromophenyl)-4,9-dioxa-1,2,6,7-tetraaza-5λ5-phosphaspiro[4.4]nona-2,7-diene

“…During our continuous efforts toward development of anticancer-relevant, heterocyclic derivatives [6][7][8], we investigated a reaction between 2-amino-5-bromobenzohydrazide 9, synthesized from 5-bromoisatoic anhydride and hydrazine hydrate according to the literature procedure [9], and methylphosphonyl dichloride 10 in the presence of triethylamine (Scheme 1). Equimolar amounts of 9 and 10 were dissolved in dry THF, three equivalents of triethylamine were added dropwise in room temperature and the reaction mixture was stirred in at room temperature for 18 h. Low-resolution mass spectrometry showed the formation of a new product with molecular mass M = 502 g/mol, and the isotopic profile revealed a product with two bromine atoms.…”

N-(4-Bromobenzyl)-2-(5,6-dimethyl-1H-benzo[d]imid-azol-2-yl)benzeneamine

“…During our continuous efforts in the investigation of various heterocyclic derivatives as possible antiproliferative and potentially anticancer compounds [20][21][22], we decided to perform a reaction between 4,5-dimethyl-1,2-phenylenediamine (13) and N-(4-bromobenzyl)-3,1-benzoxazine-2,4-dione (N-(4-bromobenzyl)-isatoic anhydride) (14) in refluxing acetic acid (Scheme 2). We found only one example of a condensation involving of N-benzylated isatoic acid with 1,2-phenylenediamine in the literature [14], and decided to investigate this reaction as a possible pathway for the synthesis of complex, biologically-relevant compounds.…”