SAR Studies of the Leupyrrins: Design and Total Synthesis of Highly Potent Simplified Leupylogs

Wosniok, Paul R.; Knopf, Christopher; Dreisigacker, Sandra; Orozco‐Rodriguez, J. Manuel; Hinkelmann, Bettina; Mueller, Peter P.; Brönstrup, Mark; Menche, Dirk

doi:10.1002/chem.202002622

Cited by 2 publications

(7 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Höfle and colleagues isolated complex γ -butyrolactone natural product, leupyrrin A1 (Entry 27) from Sorangium cellulosum and found its potent antifungal activity [ 54 ]. Menche and colleagues reported the first total synthesis of leupyrrin A1 and SAR studies of leupyrrin analogues as potent antifungal agents [ 55 , 56 ].…”

Section: Pharmacological Activities Of γ -Butyrmentioning

confidence: 99%

A Review of the Pharmacological Activities and Recent Synthetic Advances of γ-Butyrolactones

Hur

Jang

Sim

2021

IJMS

View full text Add to dashboard Cite

γ-Butyrolactone, a five-membered lactone moiety, is one of the privileged structures of diverse natural products and biologically active small molecules. Because of their broad spectrum of biological and pharmacological activities, synthetic methods for γ-butyrolactones have received significant attention from synthetic and medicinal chemists for decades. Recently, new developments and improvements in traditional methods have been reported by considering synthetic efficiency, feasibility, and green chemistry. In this review, the pharmacological activities of natural and synthetic γ-butyrolactones are described, including their structures and bioassay methods. Mainly, we summarize recent advances, occurring during the past decade, in the construction of γ-butyrolactone classified based on the bond formation in γ-butyrolactone between (i) C5-O1 bond, (ii) C4-C5 and C2-O1 bonds, (iii) C3-C4 and C2-O1 bonds, (iv) C3-C4 and C5-O1 bonds, (v) C2-C3 and C2-O1 bonds, (vi) C3-C4 bond, and (vii) C2-O1 bond. In addition, the application to the total synthesis of natural products bearing γ-butyrolactone scaffolds is described.

show abstract

Section: Pharmacological Activities Of γ -Butyrmentioning

confidence: 99%

A Review of the Pharmacological Activities and Recent Synthetic Advances of γ-Butyrolactones

Hur

Jang

Sim

2021

IJMS

View full text Add to dashboard Cite

show abstract

“…As before, our synthetic design was based on a modular total synthesis of the authentic natural products in combination with selected analogs. [18] A particular focus was placed on simplification and stabilization of the sensitive dihydrofuran segment, being prone to olefinic rearrangements. Based on a certain biological flexibility of the natural side chain, it was envisioned that the alkyliden units may be stabilized by incorporation into an aromatic moiety, leading to stabilized as well as simplified leupylogs of type 49 .…”

Section: From Leupyrrins To Leupylogsmentioning

confidence: 99%

“…Based on a certain biological flexibility of the natural side chain, it was envisioned that the alkyliden units may be stabilized by incorporation into an aromatic moiety, leading to stabilized as well as simplified leupylogs of type 49 . [18] Also, a first evaluation of natural product derivatives suggested, that the macrocyclic ring would have to be retained for biological potency. [18] …”

Section: From Leupyrrins To Leupylogsmentioning

confidence: 99%

“… [18] Also, a first evaluation of natural product derivatives suggested, that the macrocyclic ring would have to be retained for biological potency. [18] …”

Section: From Leupyrrins To Leupylogsmentioning

confidence: 99%

“…[ 13 , 14 ] However, recent findings suggest that such general scepticism may not be justified and remarkable analogs have been found that retain potent bioactivities, despite considerable simplifications. [ 15 , 16 , 17 , 18 ] Herein, we discuss three case studies focusing on the archazolids ( 1 , 2 ), [16] ajudazols ( 3 ) [17] and leupyrrins ( 4 ) [18] where rational approaches in combination with tailored synthetic strategies have led to the discovery of truncated and more readily available analogs, that retain potent biological properties of the parent natural products and may eventually help advancing the biological profile of these complex polyketides as new pharmaceutical modalities beyond the classical rule of five.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Design and Synthesis of Simplified Polyketide Analogs: New Modalities beyond the Rule of 5

Menche

2021

ChemMedChem

Self Cite

View full text Add to dashboard Cite

Natural products provide important lead structures for development of pharmaceutical agents or present attractive tools for medicinal chemistry. However, structurally complex and thus less accessible metabolites defying conventional drug‐like properties, as expressed by Pfizer's rule of five, have received less attention as medicinal leads. Traditionally, research focus has been on realizing total syntheses rather than developing more readily available analogs to resolve the critical supply issue. However, very recent studies with complex myxobacterial polyketides have demonstrated that considerable structural simplification may be realized with retention of biological potencies. The context, underlying rationale and importance of tailored synthetic strategies of three such case studies are presented, which may inspire further related activities and may eventually help exploiting the largely untapped biological potential of complex metabolites in general.

show abstract

SAR Studies of the Leupyrrins: Design and Total Synthesis of Highly Potent Simplified Leupylogs

Cited by 2 publications

References 25 publications

A Review of the Pharmacological Activities and Recent Synthetic Advances of γ-Butyrolactones

A Review of the Pharmacological Activities and Recent Synthetic Advances of γ-Butyrolactones

Design and Synthesis of Simplified Polyketide Analogs: New Modalities beyond the Rule of 5

Contact Info

Product

Resources

About