Synthesis and Anticancer Activity of New Hydroxamic Acid Containing 1,4-Benzodiazepines

Abstract

By employing an intramolecular Pd(0)-mediated ring opening of an acylnitroso-derived cycloadduct, new hydroxamic acid containing benzodiazepines have been synthesized and have demonstrated biological activity in MCF-7 and PC-3 tumor cell lines. Subsequent N-O bond reduction of the hydroxamate has provided access to amide analogs for SAR studies. During the course of our syntheses, an intermediate oxazoline-N-oxide was isolated and gave insight into the mechanism of the key Pd(0)-mediated reaction.1,4-Benzodiazepines are important biomolecules with a wide array of biological activities and therapeutic functions. Benzodiazepines are primarily known for their actions in the central nervous system. In addition to their established anxiolytic activites, 1,4-benzodiazepines also demonstrate activities as antibiotics, 1 anti-malarial, 2 and anti-HIV 3 agents. Additionally, there have been several reports of benzodiazepines as anti-cancer agents, 4 including BMS-214662, 4a a known farnesyltransferase (FTase) inhibitor, and Bz-423, 4b which has antiproliferative effects through the regulation of the c-myc protein (Figure 1).Herein we report the synthesis of 1,4-benzodiazepines via a Pd(0)-mediated ring opening of cycloadduct 3a and subsequent elaboration and evaluation of their anti-cancer activity in MCF-7 and PC-3 tumor cell lines. In contrast to the benzodiazepines disclosed in the literature, the benzodiazepines synthesized from cycloadduct 3a contain a hydroxamate embedded within the core structure. This presents the possibility of direct metal binding with the benzodiazepine ring system and makes these compounds potential inhibitors of metalloenzymes such as the aforementioned farnesyltransferase protein. 5 Whereas BMS-214662 contains an imidazole group that coordinates to zinc (II) in the FTase active site, 6 our benzodiazepine derivatives may potentially bind to the active site of FTase through a monoanionic bidentate chelation of the hydroxamate to the zinc (II) ion.Acylnitroso-derived hetero-Diels-Alder adducts, generated from the reaction of transient acylnitroso species with cyclopentadiene, are synthetically important precursors to a variety of bioactive molecules. 7 Pd(0)-mediated ring openings of acylnitroso-derived cycloadducts have been employed to provide syn-1,4-disubstituted cyclopentene derivatives. 8 Construction of the appropriately functionalized cycloadducts 3a and 3b began with commercially available mmiller1@nd.edu. NIH Public AccessAuthor Manuscript Org Lett. Author manuscript; available in PMC 2010 April 2. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 2-nitrobenzoic acid 1 (Scheme 1), which was coupled with O-benzyl hydroxylamine and subsequently deprotected and reduced under hydrogenolysis conditions to yield hydroxamic acid 2. In situ oxidation of hydroxamic acid 2 in the presence of cyclopentadiene afforded the anthranilic acid based cycloadduct, which was reacted with the appropriate sulfonyl chloride to give cycloadducts 3a and 3b in 47% and 73% yiel...

Identification of diverse modulators of central and peripheral circadian clocks by high-throughput chemical screening

“…Benzodiazepine agonists augment GABA-induced neuronal inhibition and have been used extensively as sedative drugs in humans (36). More recently, benzodiazepines have been utilized as a versatile scaffold for synthesis of derivatives with unique biological activities (37). Compound 4 showed broad period-lengthening activities in peripheral and SCN tissues ( Fig.…”

Syntheses of mycobactin analogs as potent and selective inhibitors of Mycobacterium tuberculosis

“…The resulting suspension was allowed to stir under argon for 50 h. The reaction was monitored by LCMS and after 24 h, a mixture of tri and tetra-acetylated product was observed. The crude mixture was then concentrated, co-evaporated with CHCl 3 (5 × 3 mL) and purified over iron-free silica gel 35 with 1:9, isopropyl alcohol/EtOAc as eluent, to afford 5.3 mg (70% over two steps) of the acetylated mycobactin 34 as a light, pink-colored residue: 1 H NMR (600 MHz, CDCl 3 ) δ 7.93 (d, J = 8.5 Hz, 1H), 7.59 -7.51 (m, 2H), 7.33 (d, J = 7.9 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 6.5 Hz, 1H), 5.35 (dq, J = 12.5, 6.3 Hz, 1H), 4.85 (dd, J = 10.9, 7.6 Hz, 1H), 4.60 (dd, J = 10.4, 6.3 Hz, 1H), 4.54 (dd, J = 10.9, 8.8 Hz, 1H), 4.51 - 4.46 (m, 2H), 3.97 (dd, J = 16.1, 12.0 Hz, 1H), 3.71 - 3.50 (m, 3H), 2.58 (dd, J = 14.7, 6.7 Hz, 1H), 2.48 (dd, J = 14.7, 5.6 Hz, 1H), 2.41 (s, 3H), 2.25 - 2.12 (m, 9H), 2.02 (m, 2H), 1.86 - 1.20 (m, 41H), 0.89 (t, J = 7.0 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 171.9, 171.2, 170.5, 168.6, 168.4, 167.7, 163.0, 151.1, 142.5, 131.8, 116.4, 115.3, 114.4, 69.8, 69.6, 69.5, 53.5, 52.1, 42.7, 32.1, 32.1, 31.6, 29.9, 29.9, 29.9, 29.9, 29.7, 29.6, 29.6, 29.5, 27.9, 26.3, 25.0, 22.9, 22.6, 21.7, 19.9, 18.7, 18.3, 14.4; HRMS (ESI) m/z [M+H] + : calcd for C 50 H 77 N 6 O 14 + , 985.5492; found, 985.5502.…”

Access to a Novel Class of Tetracyclic 1,4‐Benzodiazepin‐5‐ones Starting from α‐Amino Acids by Pd‐Catalyzed Amination/1,3‐Dipolar Cycloaddition as the Key Steps

“…Tricyclic 1,4-benzodiazepin-5-one systems, beyond solving anxiety and stress problems, as in the case of flumazenil (1), [3] are also antihistaminic compounds, for example, tarpane (2), [4] antibiotics, like the pyrrolo-fused abbeymicin [5] (3), and antitumor agents, such as structures 4 (Figure 1). [6] More recently, inspired by the attention given to bretazenil (5) due to its potential application in neurodegenerative diseases, [7] some tetracyclic 1,4-benzodiazepinones have appeared in the literature. These structures have the benzodiazepine nucleus fused to different hetero-and carbocycles such as pyrimidines, imidazoles, 1,2,4-triazoles, pyrazoles, benzopyrans, or naphthalenes.…”

“…Among the several procedures reported in articles and patents to synthesize 1,4-benzodiazepin-5-ones, approaches involving the formation of the 1-2 nitrogen-carbon bond as the final step are commonly used. Intramolecular cyclization of amines with carbonyls [11] or acetals/thioacetals, [12] reductive cyclization of nitro derivatives with carbonyls, [13] intramolecular 1,3-dipolar cycloadditions of azides [14] and nitrilimines [15] to alkenes and/or alkynes, aza-Wittig ringclosure of iminophosphoranyls with carbonyls, [16] intramolecular Michael addition of amines to enones, [17] intramo-lecular nucleophilic substitutions by aniline derivatives, [18] ring-opening reactions of amines on furan moieties, [19] intramolecular Pd-catalyzed cyclizations, [6,20] and the cyclization of amines with nitriles [21] on differently substituted benzamides have proven to be fruitful methodologies for promoting the formation of the nitrogen-carbon bond, eventually with the simultaneous construction of a new ring.…”