Fluorinated peptidomimetics: synthesis, conformational and biological features

Molteni, Marco; Pesenti, Cristina; Sani, Monica; Volonterio, Alessandro; Zanda, Matteo

doi:10.1016/j.jfluchem.2004.09.014

Cited by 58 publications

(17 citation statements)

References 36 publications

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“…The latter is comparable in size with the perfluoroisopropyl group 32. Rotational energy studies on ortho,ortho ′‐disubstituted biphenyl derivatives suggest that the CF 3 group supports a volume slightly larger than the volume of isopropyl,33 whereas X‐ray crystal data put its volume closer to that of an isobutyl group 34…”

Section: The Halogen Substituent Effectmentioning

confidence: 98%

The unique role of halogen substituents in the design of modern agrochemicals

2009

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The past 30 years have witnessed a period of significant expansion in the use of halogenated compounds in the field of agrochemical research and development. The introduction of halogens into active ingredients has become an important concept in the quest for a modern agrochemical with optimal efficacy, environmental safety, user friendliness and economic viability. Outstanding progress has been made, especially in synthetic methods for particular halogen-substituted key intermediates that were previously prohibitively expensive. Interestingly, there has been a rise in the number of commercial products containing 'mixed' halogens, e.g. one or more fluorine, chlorine, bromine or iodine atoms in addition to one or more further halogen atoms. Extrapolation of the current trend indicates that a definite growth is to be expected in fluorine-substituted agrochemicals throughout the twenty-first century. A number of these recently developed agrochemical candidates containing halogen substituents represent novel classes of chemical compounds with new modes of action. However, the complex structure-activity relationships associated with biologically active molecules mean that the introduction of halogens can lead to either an increase or a decrease in the efficacy of a compound, depending on its changed mode of action, physicochemical properties, target interaction or metabolic susceptibility and transformation. In spite of modern design concepts, it is still difficult to predict the sites in a molecule at which halogen substitution will result in optimal desired effects. This review describes comprehensively the successful utilisation of halogens and their unique role in the design of modern agrochemicals, exemplified by various commercial products from Bayer CropScience coming from different agrochemical areas.

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Section: The Halogen Substituent Effectmentioning

confidence: 98%

The unique role of halogen substituents in the design of modern agrochemicals

2009

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“…2) [12]. X-ray crystallographic analyses of pepstatin A and the fluorinated analog 5 bound to plasmepsin II showed a very similar conformation for both compounds demonstrating that the trifluoromethyl group can be successfully used to mimic an isobutyl moiety [12,15]. The modified inhibitor, bis-trifluoromethyl pepstatin 5 did not show any effect on proteolytic activity of HIV-protease at concentrations up to 150 µM, but a much stronger activity was found towards plasmepsin II, an aspartic protease of the malaria-causing protozoa, Plasmodium falciparum [12,15].…”

Section: The Cf 3 Moietymentioning

confidence: 95%

“…Trifluoromethyl moiety was incorporated into Pepstatin A, a subnanomolar inhibitor of many aspartyl proteases by replacing the isobutyl group to produce compound 5 (Fig. The modified inhibitor, bis-trifluoromethyl pepstatin 5 did not show any effect on proteolytic activity of HIV-protease at concentrations up to 150 µM, but a much stronger activity was found towards plasmepsin II, an aspartic protease of the malaria-causing protozoa, Plasmodium falciparum [12,15]. The substitution was performed to investigate the biological activity of the fluorinated inhibitor against several aspartyl proteases including HIV-protease, a protease for which pepstatin A has no affinity.…”

Section: The Cf 3 Moietymentioning

confidence: 99%

Fluorine Containing Molecules for Peptidomimicry: A Chemical Act to Modulate Enzymatic Activity

Oyiliagu¹,

Novalen²,

Kotra³

2006

MROC

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“…Given the ubiquitous nature of α‐amino acids in biologically active compounds, it is not surprising that there have been a number of reports describing the stereoselective incorporation of the trifluoromethyl group into simple amino acids, as well as more complex polypeptides 3. In this way, Zanda and co‐workers have shown that 2,2,2‐trifluoroethylamines can act as a nonbasic amide surrogate, and have made use of this strategy in the development of novel peptidomimetics 3a–e. This approach has also recently been employed in the development of potent and selective cathepsin K inhibitors for the treatment of osteoporosis, where the planar amide functionality of the parent compound A has been replaced with a stereogenic 2,2,2‐trifluoroethyl moiety (Scheme 1) 4.…”

Section: Methodsmentioning

confidence: 99%

Diastereoselective Reductive Amination of Aryl Trifluoromethyl Ketones and α‐Amino Esters

Hughes¹,

Devine²,

Naber³

et al. 2007

Angewandte Chemie

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The optimization of new drug entities depends on the manipulation of the potency, selectivity, adsorption, and metabolic properties of lead structures. One of the most commonly employed strategies for accomplishing these objectives involves the incorporation of fluorinated moieties into drug candidates, which often has a profound influence on their in vivo performance.[1] As such, there has been intense interest in the stereoselective inclusion of fluorinated fragments into small organic molecules.[2] One particularly important functionality employed in these endeavors is the bulky and highly electron withdrawing trifluoromethyl group, which is capable of dramatically perturbing the electronic properties of neighboring atoms. Given the ubiquitous nature of a-amino acids in biologically active compounds, it is not surprising that there have been a number of reports describing the stereoselective incorporation of the trifluoromethyl group into simple amino acids, as well as more complex polypeptides. [3] In this way, Zanda and co-workers have shown that 2,2,2-trifluoroethylamines can act as a nonbasic amide surrogate, and have made use of this strategy in the development of novel peptidomimetics. [3a-e] This approach has also recently been employed in the development of potent and selective cathepsin K inhibitors for the treatment of osteoporosis, where the planar amide functionality of the parent compound A has been replaced with a stereogenic 2,2,2-trifluoroethyl moiety (Scheme 1).[4] Amidation of the S,S isomer B of these novel a-amino acids affords particularly potent cathepsin K inhibitors, but it is likely that future applications would benefit from stereoselective access to either isomer of this intriguing class of compounds.While a number of methods for preparing the corresponding b-amino alcohols C from 1,3-oxazolines D have been described in the literature (Scheme 1), [4,5] these approaches have a number of drawbacks. Initial reports involved condensation of trifluoroacetadehyde hemiacetals and b-amino alcohols to afford approximately 1.5:1 mixtures of diastereomeric oxazolines (Scheme 1, R 4 = H).[5b] Chromatographic separation of the diastereomers, followed by stereoselective addition of an organolithium species then afforded the desired amino alcohols with excellent levels of diastereoselectivity. Recent reports from our research describe alternative protocols which avoid the need for the separation of the diastereomeric oxazolines; [4b, 5a, 6] however, these methodologies still require the use of expensive trifluoroacetaldehyde hemiacetals, are limited to substrates containing functionality which is compatible with organolithium reagents, and require oxidation of the amino alcohols to the amino acids. Mikami and co-workers have shown that 1,3-oxazolines derived from readily available trifluoroacetophenones can be converted into the same types of amino alcohols by selective reduction (Scheme 1, R 4 = Ar); [5c] however, this approach again relies on the chromatographic separation of mixtures of dias...

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Fluorinated peptidomimetics: synthesis, conformational and biological features

Cited by 58 publications

References 36 publications

The unique role of halogen substituents in the design of modern agrochemicals

The unique role of halogen substituents in the design of modern agrochemicals

Fluorine Containing Molecules for Peptidomimicry: A Chemical Act to Modulate Enzymatic Activity

Diastereoselective Reductive Amination of Aryl Trifluoromethyl Ketones and α‐Amino Esters

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