- PEGylated Bis-Sulfonamide Carbonic Anhydrase Inhibitors Can Efficiently Control the Growth of Several Carbonic Anhydrase IX-Expressing Carcinomas
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A series of aromatic/heterocyclic bis-sulfonamides were synthesized from three established aminosulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor pharmacophores, coupled with either ethylene glycol oligomeric or polymeric diamines to yield bis-sulfonamides with short or long (polymeric) linkers. Testing of novel inhibitors and their precursors against a panel of membrane-bound CA isoforms, including tumor-overexpressed CA IX and XII and cytosolic isozymes, identified nanomolar-potent inhibitors against both classes and several compounds with medium isoform selectivity in a detailed structure-activity relationship study. The ability of CA inhibitors to kill tumor cells overexpressing CA IX and XII was tested under normoxic and hypoxic conditions, using 2D and 3D in vitro cellular models. The study identified a nanomolar potent PEGylated bis-sulfonamide CA inhibitor (25) able to significantly reduce the viability of colon HT-29, breast MDA-MB231, and ovarian SKOV-3 cancer cell lines, thus revealing the potential of polymer conjugates in CA inhibition and cancer treatment.
- Akocak, Suleyman,Alam, M. Raqibul,Shabana, Ahmed M.,Sanku, Rajesh Kishore Kumar,Vullo, Daniela,Thompson, Harry,Swenson, Erik R.,Supuran, Claudiu T.,Ilies, Marc A.
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- CAIXplatins: Highly Potent Platinum(IV) Prodrugs Selective Against Carbonic Anhydrase IX for the Treatment of Hypoxic Tumors
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Hypoxia and the acidic microenvironment play a vital role in tumor metastasis and angiogenesis, generally compromising the chemotherapeutic efficacy. This provides a tantalizing angle for the design of platinum(IV) prodrugs for the effective and selective killing of solid tumors. Herein, two carbonic anhydrase IX (CAIX)-targeting platinum(IV) prodrugs have been developed, named as CAIXplatins. Based on their strong affinity for and inhibition of CAIX, CAIXplatins can not only overcome hypoxia and the acidic microenvironment, but also inhibit metabolic pathways of hypoxic cancer cells, resulting in a significantly enhanced therapeutic effect on hypoxic MDA-MB-231 tumors both in vitro and in vivo compared with cisplatin/oxaliplatin, accompanied with excellent anti-metastasis and anti-angiogenesis activities. Furthermore, the cancer selectivity indexes of CAIXplatins are 70–90 times higher than those of cisplatin/oxaliplatin with effectively alleviated side-effects.
- Cao, Qian,Ji, Liang-Nian,Mao, Zong-Wan,Pan, Zheng-Yin,Yang, Gang-Gang,Zhang, Hang,Zhou, Dan-Jie
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- Conjugates of desferrioxamine and aromatic amines improve markers of iron-dependent neurotoxicity
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Abstract: Alzheimer’s Disease (AD) is a complex neurodegenerative disorder associated in some instances with dyshomeostasis of redox-active metal ions, such as copper and iron. In this work, we investigated whether the conjugation of various aromatic amines would improve the pharmacological efficacy of the iron chelator desferrioxamine (DFO). Conjugates of DFO with aniline (DFOANI), benzosulfanylamide (DFOBAN), 2-naphthalenamine (DFONAF) and 6-quinolinamine (DFOQUN) were obtained and their properties examined. DFOQUN had good chelating activity, promoted a significant increase in the inhibition of β-amyloid peptide aggregation when compared to DFO, and also inhibited acetylcholinesterase (AChE) activity both in vitro and in vivo (Caenorhabditis elegans). These data indicate that the covalent conjugation of a strong iron chelator to an AChE inhibitor offers a powerful approach for the amelioration of iron-induced neurotoxicity symptoms. Graphic abstract: [Figure not available: see fulltext.]
- Carvalho, Rodrigo R. V.,Peres, Tanara V.,Liria, Cleber W.,Machini, M. Teresa,Aschner, Michael,Espósito, Breno P.
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p. 259 - 275
(2021/01/07)
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- Facile synthesis, single crystal analysis, and computational studies of sulfanilamide derivatives
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Antibacterial resistance is a worldwide problem. Sulfanilamide is widely used antibacterial. For the first time, we report here a simple method for the derivative synthesis of the title drugs, single crystal XRD and density functional theory (DFT) studies. The optimized molecular structure, natural bond orbital (NBO), frontier molecular orbitals (FMOs) molecular electrostatic potential studies (MEP) and Mulliken population analysis (MPA) have been performed using M06-2X/6-31G(d, p). The FT-IR spectra and thermodynamic parameters were calculated at M06-2X/6-311?+?G(2d,p) and B3LYP/6-31G(d, p) levels respectively, while, the UV–Vis analysis was performed using TD-DFT/B3LYP/6-31G(d, p) method. The experimental FT-IR spectra of both compounds were also carried out to reconfirm [sbnd]H?O[sbnd] hydrogen bonds. The DFT optimized parameters exhibiting good agreement with the experimental data. NBO analysis explored the hyper conjugative interaction and stability of title crystals, especially, reconfirmed the existence of [sbnd]H?O[sbnd] hydrogen bonds between the dimers. The FT-IR, thermodynamic parameters, MEP and MPA also revealed the hydrogen bonding detail is harmonious to XRD data. As a matter of the fact, the hydrogen bonding is a significant parameter for the understanding and design of molecular crystals, subsequently; it can also play a vital role in the supramolecular chemistry. Moreover, the global reactivity descriptors suggest that title compounds might be bioactive.
- Tahir, Muhammad Nawaz,Khalid, Muhammad,Islam, Ayesha,Ali Mashhadi, Syed Muddassir,Braga, Ataualpa A.C.
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p. 766 - 776
(2016/09/07)
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- Sulfonyl azide-mediated norbornene aziridination for orthogonal peptide and protein labeling
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We describe a new bioconjugation reaction based on the aziridination of norbornenes using electron-deficient sulfonyl azides. The reaction enables to attach various useful tags to peptides and proteins under mild conditions. This journal is
- Gattner, Michael J.,Ehrlich, Michael,Vrabel, Milan
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p. 12568 - 12571
(2014/12/11)
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- Structural study and biological evaluation of some novel 1,2,4-triazole, thiazole, and bisthiazole derivatives bearing a sulfonamide moiety
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The starting material 1,2,4-triazole derivative (3) was used to synthesize some novel condensed triazoles. Thus, treatment of compound (3) with phenyl isocyanate in refluxing pyridine furnished the novel [1,2,4]triazolo[4,3-b][1,2, 4]triazole derivative (5). Also, cyclization of compound (3) with phenyl isothiocyanate afforded the [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivative (7). Hydrazone derivative (9d) was allowed to react with some halogenated reagents such as chloroacetone, ethyl chloroacetate, and chloroacetonitrile to furnish thiazole derivatives (12), (13), and (15), respectively. In a similar manner, bishydrazone (17) was used to prepare the novel bisthiazoles (18) and (19). Some of the synthesized compounds were evaluated for their antibacterial activity.
- Al-Sehemi, Abdullah G. M.
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experimental part
p. 1991 - 2003
(2010/03/24)
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- Spectrophotometric and Titrimetric Determination of Carboxylic Acid Anhydrides
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Two redox methods are described for the determination of carboxylic acid anhydrides involving reaction with either an excess of 4-aminophenol or a measured but excessive amount of sulfanilamide and photometric titration of N-acyl-4-aminophenol with 2-iodylbenzoate by measuring the absorbance of orange-red product at 444 nm or the residual amount of sulfanilamide is determined by titration with chloramine-T in the presence of acidified potassium bromide using methyl red as visual indicator.Mixtures of certain anhydrides have also been analyzed by the 2-iodylbenzoate method.The methods are rapid, precise, and accurate.No correlation is needed if carboxylic and mineral acids are also present.Carboxylic acid chlorides also react quantitatively.
- Verma, Krishna K.,Tyagi, Pramila
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p. 2157 - 2160
(2007/10/02)
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