ABSTRACT
The looming threat of a "post-antibiotic era" has been caused by a rapid rise in antibacterial resistance and subsequent depletion of effective antibiotic agents in the clinic. An efficient strategy to address this shortfall lies in the reengineering of pre-existing and commercially available antibiotic drugs. This is exemplified by dimerization, a design concept in which two pharmacophores are covalently linked to form a new chemical entity. The cage hydrocarbons cubane (1), bicyclo[2.2.2]octane (BCO) (2), adamantane (3), and bicyclo[1.1.1]pentane (BCP) (4) present themselves as an attractive family of linkers in this regard. In this report, all four hydrocarbon cages were employed as linkers in a series of dimers based on the commercially available antibiotics trimethoprim and tedizolid. A detailed synthetic roadmap for the protection and deprotection of each pharmacophore is outlined. Several members of the trimethoprim series showed activity on par with that of their trimethoprim progenitor, although this was not the case for the tedizolid series. The design strategy outlined herein highlights the utility of the group as a platform for the rapid and modular construction of future novel antibiotics.
Subject(s)
Oxazolidinones , Trimethoprim , Trimethoprim/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , HydrocarbonsABSTRACT
A study on the potential activating role of pyridine in the electrophilic chlorination of anisole by PhICl2 has led to the discovery that soluble sources of chloride ions activate PhICl2 in the reaction at catalytic loadings, greatly increasing the rate of chlorination. It is further shown that presence of chloride increases the rate of decomposition of PhICl2 into PhI and Cl2. The specific mechanism by which chloride induces electrophilic chlorination and decomposition of PhICl2 remains an open question.
ABSTRACT
PhI(OTf)2 has been used for the past 30â years as a strong I(III) oxidant for organic and inorganic transformations. It has been reported to be generated in situ from the reactions of either PhI(OAc)2 or PhI=O with two equivalents of trimethylsilyl trifluoromethanesulfonate (TMS-OTf). In this report it is shown that neither of these reactions generate a solution with spectroscopic data consistent with PhI(OTf)2 , with supporting theoretical calculations, and thus this compound should not be invoked as the species acting as the oxidant for transformations that have been associated with its use.
ABSTRACT
With the burgeoning interest in cage motifs for bioactive molecule discovery, and the recent disclosure of 1,4-cubane-dicarboxylic acid impact sensitivity, more research into the safety profiles of cage scaffolds is required. Therefore, the impact sensitivity and thermal decomposition behavior of judiciously selected starting materials and synthetic intermediates of cubane, bicyclo[1.1.1]pentane (BCP), and bicyclo[2.2.2]octane (BCO) were evaluated via hammer test and sealed cell differential scanning calorimetry, respectively. Iodo-substituted systems were found to be more impact sensitive, whereas hydroxymethyl substitution led to more rapid thermodecomposition. Cubane was more likely to be impact sensitive with these substituents, followed by BCP, whereas all BCOs were unresponsive. The majority of derivatives were placed substantially above Yoshida thresholds-a computational indicator of sensitivity.
ABSTRACT
The replacement of one chemical motif with another that is broadly similar is a common method in medicinal chemistry to modulate the physical and biological properties of a molecule (i.e., bioisosterism). In recent years, bioisosteres such as cubane and bicyclo[1.1.1]pentane (BCP) have been used as highly effective phenyl mimics. Herein, we show the successful incorporation of a range of phenyl bioisosteres during the open-source optimization of an antimalarial series. Cubane (19) and closo-carborane (23) analogues exhibited improved in vitro potency against Plasmodium falciparum compared to the parent phenyl compound; however, these changes resulted in a reduction in metabolic stability; unusually, enzyme-mediated oxidation was found to take place on the cubane core. A BCP analogue (22) was found to be equipotent to its parent phenyl compound and showed significantly improved metabolic properties. While these results demonstrate the utility of these atypical bioisosteres when used in a medicinal chemistry program, the search to find a suitable bioisostere may well require the preparation of many candidates, in our case, 32 compounds.
Subject(s)
Antimalarials/chemical synthesis , Boron Compounds/chemistry , Bridged Bicyclo Compounds/chemical synthesis , Drug Design , Antimalarials/chemistry , Antimalarials/pharmacology , Antimalarials/toxicity , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacology , Bridged Bicyclo Compounds/toxicity , Cell Survival/drug effects , Chemistry, Pharmaceutical , Hep G2 Cells , Humans , Molecular Structure , Plasmodium falciparum/drug effectsABSTRACT
The highly strained cubylmethyl radical undergoes one of the fastest radical rearrangements known (reported k = 2.9 × 1010 s-1 at 25 °C) through scission of two bonds of the cube. The rearrangement has previously been used as a mechanistic probe to detect radical-based pathways in enzyme-catalyzed C-H oxidations. This paper reports the discovery of highly selective cytochrome P450-catalyzed methylcubane oxidations which notionally proceed via cubylmethyl radical intermediates yet are remarkably free of rearrangement. The bacterial cytochrome P450 CYP101B1 from Novosphingobium aromaticivorans DSM 12444 is found to hydroxylate the methyl group of a range of methylcubane substrates containing a regio-directing carbonyl functionality at C-4. Unlike other reported P450-catalyzed methylcubane oxidations, the designed methylcubanes are hydroxylated with high efficiency and selectivity, giving cubylmethanols in yields of up to 93%. The lack of cubane core ring-opening implies that the cubylmethyl radicals formed during these CYP101B1-catalyzed hydroxylations must have very short lifetimes, of just a few picoseconds, which are too short for them to manifest the side reactivity characteristic of a fully equilibrated P450 intermediate. We propose that the apparent ultrafast radical rebound can be explained by a mechanism in which C-H abstraction and C-O bond formation are merged into a dynamically coupled process, effectively bypassing a discrete radical intermediate. Related dynamical phenomena can be proposed to predict how P450s may achieve various other modes of reactivity by controlling the formation and fate of radical intermediates. In principle, dynamical ideas and two-state reactivity are each individually able to explain apparent ultrashort radical lifetimes in P450 catalysis, but they are best considered together.
ABSTRACT
The highly oxygenated pimarane diterpenoids basimarols A, B, and C (3-5) were isolated from the plant species Basilicum polystachyon, which was collected within the Australian arid zone. Structure elucidation was performed using a suite of spectroscopic techniques, including X-ray crystallography. Anticancer and anti-DENV activity of 3-5 was explored, but only limited activity was observed. More extensive antiviral evaluation of stachyonic acid A (1), which was also isolated from B. polystachyon, revealed broad spectrum antiviral activity against West Nile virus (Kunjin strain, WNVKun) and human influenza viruses H1N1 and H3N2.
Subject(s)
Abietanes/isolation & purification , Antineoplastic Agents, Phytogenic/isolation & purification , Antiviral Agents/isolation & purification , Lamiaceae/chemistry , Abietanes/chemistry , Abietanes/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cell Line, Tumor , HumansABSTRACT
The cubane phenyl ring bioisostere paradigm was further explored in an extensive study covering a wide range of pharmaceutical and agrochemical templates, which included antibiotics (cefaclor, penicillin G) and antihistamine (diphenhydramine), a smooth muscle relaxant (alverine), an anaesthetic (ketamine), an agrochemical instecticide (triflumuron), an antiparasitic (benznidazole) and an anticancer agent (tamibarotene). This investigation highlights the scope and limitations of incorporating cubane into bioactive molecule discovery, both in terms of synthetic compatibility and physical property matching. Cubane maintained bioisosterism in the case of the Chagas disease antiparasitic benznidazole, although it was less active in the case of the anticancer agent (tamibarotenne). Application of the cyclooctatetraene (COT) (bio)motif complement was found to optimize benznidazole relative to the benzene parent, and augmented anticancer activity relative to the cubane analogue in the case of tamibarotene. Like all bioisosteres, scaffolds and biomotifs, however, there are limitations (e.g. synthetic implementation), and these have been specifically highlighted herein using failed examples. A summary of all templates prepared to date by our group that were biologically evaluated strongly supports the concept that cubane is a valuable tool in bioactive molecule discovery and COT is a viable complement.
Subject(s)
Benzene/chemistry , Cyclooctanes/chemistry , Nitroimidazoles/chemistry , Antineoplastic Agents/chemistry , Benzoates/chemistry , Molecular Structure , Tetrahydronaphthalenes/chemistryABSTRACT
Despite the difficulty in administering a safe dose regimen and reports of emerging resistance, warfarin (1) remains the most widely-used oral anticoagulant for the prevention and treatment of thrombosis in humans globally. Systematic substitution of the warfarin phenyl ring with either 1,3,5,7-cyclooctatetraene (COT) (2), cubane (3), cyclohexane (4) or cyclooctane (5) and subsequent evaluation against the target enzyme, vitamin K epoxide reductase (VKOR), facilitated interrogation of both steric and electronic properties of the phenyl pharmacophore. The tolerance of VKOR to further functional group modification (carboxylate 14, PTAD adduct 15) was also investigated. The results demonstrate the importance of both annulene conferred π-interactions and ring size in the activity of warfarin.
Subject(s)
Anticoagulants/pharmacokinetics , Anticoagulants/therapeutic use , Warfarin/pharmacokinetics , Warfarin/therapeutic use , Anticoagulants/pharmacology , Humans , Warfarin/pharmacologyABSTRACT
Stachyonic acid A, arising from the first in-depth phytochemical investigation of the herb Basilicum polystachyon, was found to display potent inhibitory activity against dengue virus, with limited cytotoxicity. Andrographolide, a known dengue virus inhibitor and closely related labdane-type diterpene, is structurally more complex but displayed poor antiviral activity in the PRNT assay, and increased cytotoxicity in comparison. Furthermore, a Diels-Alder reaction with PTAD identified the active pharmacophore of stachyonic acid to be the conjugated diene.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Dengue Virus/drug effects , Dengue/drug therapy , Diterpenes/chemistry , Diterpenes/pharmacology , Drug Discovery , Humans , Lamiaceae/chemistry , Models, Molecular , Virus Replication/drug effectsABSTRACT
Cubane was recently validated as a phenyl ring (bio)isostere, but highly strained caged carbocyclic systems lack π character, which is often critical for mediating key biological interactions. This electronic property restriction associated with cubane has been addressed herein with cyclooctatetraene (COT), using known pharmaceutical and agrochemical compounds as templates. COT either outperformed or matched cubane in multiple cases suggesting that versatile complementarity exists between the two systems for enhanced bioactive molecule discovery.
ABSTRACT
The scope and limitations of Eaton's rhodium(I)-catalyzed valence isomerization of cubane to cyclooctatetraene (COT) were investigated in the context of functional group tolerability, multiple substitution modes and the ability of cubane-alcohols to undergo one-pot tandem Ley-Griffith Wittig reactions in the absence of a transition metal catalyst.
ABSTRACT
The first enantioselective synthesis of (R)-2-cubylglycine, an analogue of (R)-2-phenylglycine in which the phenyl ring has been replaced by cubane, is disclosed. The key step was a telescoped Strecker reaction using (S)-2-amino-2-phenylethanol as a chiral auxiliary. Exploration of an alternative synthetic approach resulted in unprecedented cubane C-H insertion.