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Alternative Tumor-Targeting Strategies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Despite extensive clinical evaluation of the original combretastatin compound along with some close analogues, efficacy in the clinic proved disappointing. This led to the investigation of a number of other analogues including ZD6126 developed by AstraZeneca, although clinical trials were eventually halted due to an unexpected cardiotoxicity. Another analogue, AVE8062 (ombrabulin), developed by Sanofi-Aventis, was granted Orphan Drug status by the EMA in 2011. However, development was discontinued after disappointing results in Phase III clinical trials.
Drug Development with Magnetic Resonance Imaging
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
DCE-MRI has been used to assess the effects of several vascular disrupting agents in preclinical studies and in early phase clinical trials. DCE-MRI studies were conducted in rodent tumor models prior to phase 1 studies for both CA-4-P (50,65) and ZD6126 (66,67). For CA-4-P, Ktrans, and IAUC in P22 carcinosarcomas implanted subcutaneously on the flank of male rats decreased by greater than 50% at one hour and six hours after 10 mg/kg, 30 mg/kg, or 100 mg/kg doses. At 24 hours after treatment, Ktrans and IAUC remained decreased in the 30 mg/kg and 100 mg/kg groups, but returned to pretreatment levels in the 10 mg/kg group. In phase 1 clinical studies (50,68,69), Ktrans and/or IAUC decreased by more than 50% four to six hours after treatment with CA-4-P at doses greater than 50 mg/m2 in a third of the patients studied. In the one study where Ktrans and IAUC were also measured 24 hours after treatment in 14 patients (50), the decrease was less than at four to six hours after treatment in two-thirds of the subjects (and 75% of the subjects with a decrease greater than 50% at 4–6 hours after treatment). Thus, the preclinical and clinical data were consistent and considered to provide proof that this drug has tumor antivascular activity. Preclinical studies of ZD6126 (66,67) showed a dose-dependent decrease in IAUC 24 hours after treatment with decreases as large as 90% at the highest doses. The dose-dependent decrease in IAUC correlated with the extent of treatment-induced necrosis, but there was little or no delay in tumor growth (66). In the phase 1 clinical study (66), IAUC decreased by more than 50% in a third of the patients treated at 56 mg/m2 or higher. Similar to the case for CA-4-P, preclinical studies translated well to the clinic and DCE-MRI was considered to provide a useful endpoint for quantifying ZD6126 antivascular effects in human tumors.
Tertiary sulphonamide derivatives as dual acting small molecules that inhibit LSD1 and suppress tubulin polymerisation against liver cancer
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Lijuan Ding, Feng Wei, Nanya Wang, Yue Sun, Qiang Wang, Xia Fan, Ling Qi, Shudong Wang
Microtubules as ubiquitous fibrous structures in eukaryotic cells are the key component of cytoskeleton1. They are spherical proteins composed of α- and β-tubulin heterodimers, which display significant functions in the formation and maintenance of cell shape, intracellular transport, cell division and organellar movement2. Benzenesulphonamide derivative BA-3P was synthesised as a anti-prostate cancer agent targeting tubulin2. Furthermore, several microtubule-binding drugs (ZD6126, CA-1P, AVE8062, CA-4P, BNC-105p, Paclitaxel and Vinblastine) have been successfully employed in clinical use (Figure 1)3. These microtubule-targeting agents have the great potential to be anticancer drugs, which could affect the process of microtubule homoeostasis, induce tumour cell apoptosis and arrest cell cycle4. Hence, the development of microtubule-binding agents is a hot field in the research of novel antitumor drugs.
Biological evaluation of benzosuberones
Published in Expert Opinion on Therapeutic Patents, 2018
Haider Behbehani, Kamal M. Dawood, Thoraya A. Farghaly
Benzosuberan (benzocycloheptane) is an attractive fused-dicarbocyclic scaffold that constitutes the building block of various natural products of potential medicinal and pharmaceutical applications [1]. Benzosuberone derivatives have remarkable broad-spectrum biological activities such as antitumor, antimicrobial, anti-inflammatory, antiestrogenic, antipyretic, antiulcer, anti-malarial, CNS-depressant, CNS stimulant, anticonvulsant, and antiplatelet aggregation activities [2–7]. Some natural products that contain the benzosuberone scaffold are Colchicine, Theaflavin, Bussealin E, Demethylsalvicanol, Brussonol, and Feveline as depicted in Figure 1. These natural products were clinically proven as anticancer agents [8–14]. Colchicine was the first drug reported to function through a tubulin-binding mechanism in 1930 [15] and has been used in the treatment of gout since 1950 [16]. Further examples of benzosuberan-based natural products are ZD6126; has been halted in human clinical trials [17–19], ar-himachalene [20] and the isopavine derivatives (amurensinine and roelactamine) were useful as neurological disorders inhibitors [21,22]. Some tricyclic dibenzosuberone derivatives like imipramine [23], amitriptyline [24], and noxiptiline [25] (Figure 2) were reported as antidepressants where they mostly affect the autonomic and central nervous systems and were used as first-line drugs in treating depressive disorders. Chalcones were also reported as effective antioxidant, anti-inflammatory, antitumor agents, and cell proliferation inhibitors [26–29]. In this regard, several benzosuberone-based chalcones were found to possess variety of biological potencies. The current survey revealed very interesting data about the applications of benzosuberones and their heterocyclic-fused rings as potential medicinal and pharmaceutical compounds. It is worthy to mention that this review discloses the first intensive report on the biological activities of benzosuberones and their fused rings reported in the literature until the first quarter of 2017.
Design, synthesis, and biological screening of a series of 4′-fluoro-benzotriazole-acrylonitrile derivatives as microtubule-destabilising agents (MDAs)
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Federico Riu, Roberta Ibba, Stefano Zoroddu, Simona Sestito, Michele Lai, Sandra Piras, Luca Sanna, Valentina Bordoni, Luigi Bagella, Antonio Carta
MT-targeting drugs are commonly divided into microtubule-destabilising agents (MDAs), e.g. colchicine or vinblastine, and microtubule-stabilising agents (MSAs), such as paclitaxel or epothilones. MDAs prevent tubulin polymerisation and the consequent MT assembly; differently, MSAs promote tubulin polymerisation.10 Focussing on MDAs therapy, their clinical challenges include low therapeutic windows and innate or acquired drug resistance. Some tumours thought to have microtubule-independent trafficking of key oncogenic proteins seem not to respond to MDAs at all, such as renal cell carcinomas.11 One of the most famous MDAs is colchicine (Figure 2), an alkaloid mainly indicated as a treatment of inflammatory diseases, such as recurrent pericarditis treatment,12 gout and familial Mediterranean fever.13,14 Colchicine interacts with tubulin heterodimer in the so-called colchicine-binding site (CBS), located at the interface between α- and β-tubulin.15 Colchicine-tubulin interaction makes the microtubule polymerisation process energetically unfavourable and prevents the microtubule growth by sterically blocking further addition of tubulin dimers at the plus end.16 Colchicine was also shown to alter the mitochondrial membrane potential and release pro-apoptotic factors like caspases, leading to apoptotic cell death.17 Despite its multimodal activity, its therapeutic potential against cancer is restrained due to its low therapeutic index. Also, compound ZD6126, a water-soluble phosphate prodrug, initially selected as a gold alternative to colchicine (Figure 2), did not succeeded further as an anticancer agent due to cardiotoxicity and other severe side effects.18 Although colchicine failure, multiple efforts were made to develop clinically potent colchicine-binding site inhibitors (CBSIs). CBSIs are some of the most interesting MDAs as they target the β-subunit of tubulin in its curved and unassembled form and prevent it from adopting a microtubular straight structure.19,20 So far, combretastatin A-4 is arguably the most successful representative of the CBSI family.21,22