Publications

26 publications

26. Form Follows Function: Designer Chemistry at the 52nd Bürgenstock Conference

P. Heretsch

Angew. Chem. Int. Ed. 2017, 56, 8933-8936; Angew. Chem. 2017, 129, 9059-9062.

http://onlinelibrary.wiley.com/doi/10.10 ...http://onlinelibrary.wiley.com/doi/10.10 ...

The 52nd Bürgenstock Conference on Stereochemistry took place from April 30–May 4, 2017, and showed how chemistry and design go hand-in-hand (as reflected in the image of the Bauhausarchiv in Berlin). In this Conference Report, Philipp Heretsch outlines the program.

25. Synthesis of Secosterols as an Arena for C–H Functionalization and C–C Manipulation Tactics

R.C. Heinze, P. Heretsch

Synlett 2017, 28, 1127-1133.

https://www.thieme-connect.de/products/e ...

The chemical synthesis of secosterols is an arena for the application of C–H functionalization methods as well as C–C manipulations. Studies on the innate reactivity of synthetic intermediates to undergo C–C scissions and rearrangements can shed light on biosynthetic pathways, or, provide proof for biosynthetic proposals. Examples of the authors work (synthesis of the 14,15-secosterol strophasterol A), as well as examples from current literature (Tian’s synthetic work on 13,14:14,15-disecosterols glaucogenins C and D, and Baran’s synthesis of 9,10-secosterol cortistatin A) are discussed.

24. Synthesis of Strophasterol A Guided by a Proposed Biosynthesis and Innate Reactivity

R.C. Heinze, D. Lentz, P. Heretsch

Angew. Chem. Int. Ed. 2016, 55, 11656-11659; Angew. Chem. 2016, 128, 11828-11831

http://onlinelibrary.wiley.com/doi/10.10 ...http://onlinelibrary.wiley.com/doi/10.10 ...

The synthesis of strophasterol A, a moderator of endoplasmatic reticulum (ER) stress in Alzheimer's disease, and the first member of a structurally unprecedented class of secosterols, was achieved through the implementation of a key step of its proposed biosynthesis and two C−H oxidations. Analysis of the innate reactivity of the intermediates enabled the identification of a novel way to prepare an α-chloro-γ-hydroxy-δ-keto enone, as well as its vinylogous α-ketol rearrangement to a δ-keto carboxylic acid.

23. Total Synthesis of Δ12-Prostaglandin J3: Evolution of Synthetic Strategies to a Streamlined Process

K.C. Nicolaou, K.K. Pulukuri, R. Yu, S. Rigol, P. Heretsch, C.I. Grove, C.R.H. Hale, A.E. Marrouni

Chem. Eur. J. 2016, 22, 8559-8570

http://onlinelibrary.wiley.com/doi/10.10 ...

The total synthesis of Δ12-prostaglandin J3 (Δ12-PGJ3, 1), a reported leukemia stem cell ablator, through a number of strategies and tactics is described. The signature cross-conjugated dienone structural motif of 1 was forged by an aldol reaction/dehydration sequence from key building blocks enone 13 and aldehyde 14, whose lone stereocenters were generated by an asymmetric Tsuji–Trost reaction and an asymmetric Mukaiyama aldol reaction, respectively. During this program, a substituent-governed regioselectivity pattern for the Rh-catalyzed C−H functionalization of cyclopentenes and related olefins was discovered. The evolution of the synthesis of 1 from the original strategy to the final streamlined process proceeded through improvements in the construction of both fragments 13 and 14, exploration of the chemistry of the hitherto underutilized chiral lactone synthon 57, and a diastereoselective alkylation of a cyclopentenone intermediate. The described chemistry sets the stage for large-scale production of Δ12-PGJ3 and designed analogues for further biological and pharmacological studies.

22. Synthesis and Biological Investigation of Δ12-Prostaglandin J3 (Δ12-PGJ3) Analogues and Related Compounds

K.C. Nicolaou, K.K. Pulukuri, S. Rigol, P. Heretsch, R. Yu, C.I. Grove, C.R.H. Hale, A.E. Marrouni, V. Fetz, M. Brönstrup, M. Aujay, J. Sandoval, J. Gavrilyuk

J. Am. Chem. Soc. 2016, 138, 6550-6560

http://pubs.acs.org/doi/abs/10.1021/jacs ...

A series of Δ12-prostaglandin J3 (Δ12-PGJ3) analogues and derivatives were synthesized employing an array of synthetic strategies developed specifically to render them readily available for biological investigations. The synthesized compounds were evaluated for their cytotoxicity against a number of cancer cell lines, revealing nanomolar potencies for a number of them against certain cancer cell lines. Four analogues (2, 11, 21, and 27) demonstrated inhibition of nuclear export through a covalent addition at Cys528 of the export receptor Crm1. One of these compounds (i.e., 11) is currently under evaluation as a potential drug candidate for the treatment of certain types of cancer. These studies culminated in useful and path-pointing structure activity relationships (SARs) that provide guidance for further improvements in the biological/pharmacological profiles of compounds within this class.

21. The Veratrum and Solanum Alkaloids

P. Heretsch, A. Giannis

The Alkaloids – Chemistry and Biology 2015, 74, 201-232

http://www.sciencedirect.com/science/art ...

This survey on steroidal alkaloids of the Veratrum and Solanum family isolated between 1974 and 2014 includes 187 compounds and 197 references. New developments in the chemistry and biology of this family of natural products with a special focus on the medicinal relevance of the jervanine alkaloid cyclopamine are discussed.

20. Total Synthesis of Trioxacarcin DC-45-A2

K.C. Nicolaou, Q. Cai, B. Qin, M.T. Petersen, R.J.T. Mikkelsen, P. Heretsch

Angew. Chem. Int. Ed. 2015, 54, 3074-3078; Angew. Chem. 2015, 127, 3117-3121

http://onlinelibrary.wiley.com/doi/10.10 ...http://onlinelibrary.wiley.com/doi/10.10 ...

An enantioselective total synthesis of trioxacarcin DC-45-A2 (1) featuring a novel Lewis acid-induced cascade rearrangement of epoxyketone 6 to forge the polyoxygenated 2,7-dioxabicyclo[2.2.1]heptane core of the molecule is described.

19. Synthesis and Biological Evaluation of QRSTUVWXYZA′ Domains of Maitotoxin

K.C. Nicolaou, P. Heretsch, T. Nakamura, A. Rudo, M. Murata, K. Konoki

J. Am. Chem. Soc. 2014, 136, 16444-16451

http://pubs.acs.org/doi/abs/10.1021/ja50 ...

The synthesis of QRSTUVWXYZA′ domains 7, 8, and 9 of the highly potent marine neurotoxin maitotoxin (1), the largest secondary metabolite isolated to date, is described. The devised synthetic strategy entailed a cascade Takai–Utimoto ester olefination/ring closing metathesis to construct ring Y, a hydroxydithioketal cyclization/methylation sequence to cast ring X, a Horner–Wadsworth–Emmons coupling of WXYZA′ ketophosphonate 11 with QRSTU aldehyde 12 to form enone 10, and a reductive hydroxyketone ring closure to forge ring V. 2D NMR spectroscopic analysis and comparison of 13C chemical shifts with those of the corresponding carbons of maitotoxin revealed close similarities supporting the originally assigned structure of this region of the natural product. Biological evaluations of various synthesized domains of maitotoxin in this and previous studies from these laboratories led to fragment structure–activity relationships regarding their ability to inhibit maitotoxin-elicited Ca2+ influx in rat C6 glioma cells.

18. Total Synthesis of Δ12-Prostaglandin J3, a Highly Potent and Selective Antileukemic Agent

K.C. Nicolaou, P. Heretsch, A.E. Marrouni, C.R.H. Hale, K.K. Pulukuri, A.K. Kudva, V. Narayan, K.S. Prabhu

Angew. Chem. Int. Ed. 2014, 53 10443-10447; Angew. Chem. 2014, 126 10611-10615

http://onlinelibrary.wiley.com/doi/10.10 ...http://onlinelibrary.wiley.com/doi/10.10 ...

A catalytic asymmetric total synthesis of the potent and selective antileukemic Δ12-prostaglandin J3 (Δ12-PGJ3) is described. The convergent synthesis proceeded through intermediates 2 and 3, formed enantioselectively from readily available starting materials and coupled through an aldol reaction followed by dehydration to afford stereoselectively the cyclopentenone alkylidene structural motif of the molecule.

17. C–H-Functionalization logic guides the synthesis of a carbacyclopamine analog

S. Rabe, J. Moschner, M. Bantzi, P. Heretsch

Beilstein J. Org. Chem. 2014, 10, 1564-1569.

http://www.beilstein-journals.org/bjoc/s ...

The chemical synthesis of carbacyclopamine analog 2, a cyclopamine analog with an all-carbon E-ring, is reported. The use of C–H-functionalization logic and further metal-catalyzed transformations allows for a concise entry to this new class of acid-stable cyclopamine analogs.

16. Cyclopamine and Congeners

P. Heretsch,* A. Giannis

Natural Products in Medicinal Chemistry: Methods and Principles in Medicinal Chemistry, Wiley-VCH, Weinheim 2014, 545-563

http://onlinelibrary.wiley.com/doi/10.10 ...

In recent years it became more and more evident that conserved embryonic signaling path-ways such as Hedgehog (Hh), Wingless (Wnt), and Notch play an important role in the devel-opment of human cancer. Especially, the hedgehog signaling pathway has moved into the focus for its ability to regulate pathologic processes including tumor growth, self-renewal, and resistance to chemotherapy. Preclinical data in various tumor types have proven the role of hedgehog signaling in cancers of the skin, brain, lung, breast, prostate, colon, as well as hematologic malignancies including leukemia, lymphoma, and multiple myeloma. Encouraged by these promising insights, several natural as well as designed compounds that regulate the hedgehog signaling pathway at different stages have been identified, but still, cyclopamine, the first inhibitor of the hedgehog pathway discovered plays a dominant role in ongoing research and as a lead in the development of clinical drug candidates. On the following pages, the story of cyclopamine and the hedgehog signaling pathway as well as the application of cyclopamine and congeners in the treatment of certain types of cancer and recent developments in the field of hedgehog modulation will be presented and discussed.

15. Cyclopamine analogs bearing exocyclic methylenes are highly potent and acid-stable inhibitors of hedgehog signaling

J. Moschner, A. Chentsova, N. Eilert, I. Rovardi, P. Heretsch

Beilstein J. Org. Chem. 2013, 9, 2328-2335.

http://www.beilstein-journals.org/bjoc/s ...

The chemical synthesis and biological evaluation of new cyclopamine analogs bearing exocyclic methylenes in different positions is described. Bis-exo-cyclopamine 6 was identified as a potent inhibitor of the Gli1-dependent luciferase expression in Shh-LIGHTII cells. An extension of this study to F-ring-modified structures shows the necessity of a rigidly positioned nitrogen atom for bioactivity as well as the presence of the C21 methyl group for acid stability and bioactivity.

14. Synthesis and antioxidant evaluation of (S,S)- and (R,R)-secoisolariciresinol diglucosides (SDGs)

14. O.P. Mishra, N. Simmons, S. Tyagi, R. Pietrofesa, V. Shuvaev, R.A. Valiulin, P. Heretsch, K.C. Nicolaou, M. Christofidou-Solomidou

Bioorg. Med. Chem. Lett. 2013, 15, 5325-5328

http://www.sciencedirect.com/science/art ...

Secoisolariciresinol diglucosides (SDGs) (S,S)-SDG-1 (major isomer in flaxseed) and (R,R)-SDG-2 (minor isomer in flaxseed) were synthesized from vanillin via secoisolariciresinol (6) and glucosyl donor 7 through a concise route that involved chromatographic separation of diastereomeric diglucoside derivatives (S,S)-8 and (R,R)-9. Synthetic (S,S)-SDG-1 and (R,R)-SDG-2 exhibited potent antioxidant properties (EC50 = 292.17 ± 27.71 μM and 331.94 ± 21.21 μM, respectively), which compared well with that of natural (S,S)-SDG-1 (EC50 = 275.24 ± 13.15 μM). These values are significantly lower than those of ascorbic acid (EC50 = 1129.32 ± 88.79 μM) and α-tocopherol (EC50 = 944.62 ± 148.00 μM). Compounds (S,S)-SDG-1 and (R,R)-SDG-2 also demonstrated powerful scavenging activities against hydroxyl [natural (S,S)-SDG-1: 3.68 ± 0.27; synthetic (S,S)-SDG-1: 2.09 ± 0.16; synthetic (R,R)-SDG-2: 1.96 ± 0.27], peroxyl [natural (S,S)-SDG-1: 2.55 ± 0.11; synthetic (S,S)-SDG-1: 2.20 ± 0.10; synthetic (R,R)-SDG-2: 3.03 ± 0.04] and DPPH [natural (S,S)-SDG-1: EC50 = 83.94 ± 2.80 μM; synthetic (S,S)-SDG-1: EC50 = 157.54 ± 21.30 μM; synthetic (R,R)-SDG-2: EC50 = 123.63 ± 8.67 μM] radicals. These results confirm previous studies with naturally occurring (S,S)-SDG-1 and establish both (S,S)-SDG-1 and (R,R)-SDG-2 as potent antioxidants and free radical scavengers for potential in vivo use.

13. General Synthetic Approach to Functionalized Dihydrooxepines

K.C. Nicolaou, R. Yu, L. Shi, Q. Cai, M. Lu, P. Heretsch

Org. Lett. 2013, 15, 1994-1997.

http://pubs.acs.org/doi/abs/10.1021/ol40 ...

A three-step sequence to access functionalized 4,5-dihydrooxepines from cyclohexenones has been developed. This approach features a regioselective Baeyer–Villiger oxidation and subsequent functionalization via the corresponding enol phosphate intermediate.

12. Microbiologically Produced Carboxylic Acids Used as Building Blocks in Organic Synthesis

A. Aurich, R. Specht, R. A. Müller, U. Stottmeister, V. Yovkova, C. Otto, M. Holz, G. Barth, P. Heretsch, F.A. Thomas, D. Sicker, A. Giannis

Reprogramming Microbial Metabolic Pathways, Subcellular Biochemistry 2012, 64, 391-423.

http://link.springer.com/chapter/10.1007 ...

Oxo- and hydroxy-carboxylic acids are of special interest in organic synthesis. However, their introduction by chemical reactions tends to be troublesome especially with regard to stereoselectivity. We describe herein the biotechnological preparation of selected oxo- and hydroxycarboxylic acids under “green” conditions and their use as promising new building blocks. Thereby, our biotechnological goal was the development of process fundamentals regarding the variable use of renewable raw materials, the development of a multi purpose bioreactor and application of a pilot plant with standard equipment for organic acid production to minimize the technological effort. Furthermore the development of new product isolation procedures, with the aim of direct product recovery, capture of products or single step operation, was necessary. The application of robust and approved microorganisms, also genetically modified, capable of using a wide range of substrates as well as producing a large spectrum of products, was of special importance. Microbiologically produced acids, like 2-oxo-glutaric acid and 2-oxo-d-gluconic acid, are useful educts for the chemical synthesis of hydrophilic triazines, spiro-connected heterocycles, benzotriazines, and pyranoic amino acids. The chiral intermediate of the tricarboxylic acid cycle, (2R,3S)-isocitric acid, is another promising compound. For the first time our process provides large quantities of enantiopure trimethyl (2R,3S)-isocitrate which was used in subsequent chemical transformations to provide new chiral entities for further usage in total synthesis and pharmaceutical research.

11. Synthesis and Biological Evaluation of Epidithio-, Epitetrathio-, and bis-(Methylthio)diketopiperazines: Synthetic Methodology, Enantioselective Total Synthesis of Epicoccin G, 8,8′-epi-ent-Rostratin B, Gliotoxin, Gliotoxin G, Emethallicin E, ...

K.C. Nicolaou, M. Lu, S. Totokotsopoulos, P. Heretsch, D. Giguère, Y.-P. Sun, D. Sarlah, T.H. Nguyen, I.C. Wolf, D.F. Smee, C.W. Day, S. Bopp, E.A. Winzeler

J. Am. Chem. Soc. 2012, 134, 17320-17332

http://pubs.acs.org/doi/abs/10.1021/ja30 ...

An improved sulfenylation method for the preparation of epidithio-, epitetrathio-, and bis-(methylthio)diketopiperazines from diketopiperazines has been developed. Employing NaHMDS and related bases and elemental sulfur or bis[bis(trimethylsilyl)amino]trisulfide (23) in THF, the developed method was applied to the synthesis of a series of natural and designed molecules, including epicoccin G (1), 8,8′-epi-ent-rostratin B (2), gliotoxin (3), gliotoxin G (4), emethallicin E (5), and haematocin (6). Biological screening of selected synthesized compounds led to the discovery of a number of nanomolar antipoliovirus agents (i.e., 46, 2,2′-epi-46, and 61) and several low-micromolar anti-Plasmodium falciparum lead compounds (i.e., 46, 2,2′-epi-46, 58, 61, and 1).

10. N-Sulfinyl benzenesulfonamide

P. Heretsch, A. Giannis

Encyclopedia of Reagents for Organic Synthesis 2012, John Wiley & Sons, Ltd.

http://onlinelibrary.wiley.com/doi/10.10 ...

(reagent used in a wide array of ene-reactions and cycloadditions) Physical Data: mp 73 °C; bp 110–120 °C at 0.004 mbar. Solubility: soluble in benzene, toluene, diethyl ether, chloroform, and several other aprotic solvents. Form Supplied in: pale yellow needles; not commercially available. Preparative Methods: prepared from benzenesulfonamide by heating in thionyl chloride with catalytic amounts of TMSCl, or from N,N-dichlorobenzene sulfonamide, or the Na salt of N-chlorobenzenesulfonamide,1 or by treating benzenesulfonamide with N-(chlorosulfinyl)imidazole.2 Purification: vacuum distillation at 0.004 mbar, then recrystallization from toluene. Handling, Storage, and Precautions: store under nitrogen atmosphere and refrigerate. Do not heat above 170 °C during distillation. Incompatible with protic solvents. Decomposes on prolonged exposure to air and humidity

9. Enantioselective Dichlorination of Allylic Alcohols

K.C. Nicolaou, N.L. Simmons, Y. Ying, P. Heretsch, J.S. Chen

J. Am. Chem. Soc. 2011, 133 8134-8137

http://pubs.acs.org/doi/abs/10.1021/ja20 ...

The development of an enantioselective allylic alcohol dichlorination catalyzed by dimeric cinchona alkaloid derivatives and employing aryl iododichlorides as chlorine sources is reported. Reaction optimization, exploration of the substrate scope, and a model for stereoinduction are presented.

8. Exo-Cyclopamine–a stable and potent inhibitor of hedgehog-signaling

P. Heretsch, A. Büttner, L. Tzagkaroulaki, S. Zahn, B. Kirchner, A. Giannis

Chem. Commun. 2011, 47, 7362-7364

http://pubs.rsc.org/en/Content/ArticleLa ...

The combination of theoretical and computational studies with organic synthesis and biological investigations has led to exo-cyclopamine. This stable and highly potent derivative of cyclopamine promises big potential as an experimental drug against several types of human cancer.

7. Modulators of the hedgehog signaling pathway

P. Heretsch, L. Tzagkaroulaki, A. Giannis

Bioorg. Med. Chem. 2010, 18, 6613-6624

http://www.sciencedirect.com/science/art ...

Since its discovery by C. Nüsslein-Volhard and E. F. Wieschaus, hedgehog (hh) signaling has come a long way. Today it is regarded as a key regulator in embryogenesis where it governs processes like cell proliferation, differentiation, and tissue patterning. Furthermore, in adults it is involved in the maintenance of stem cells, and in tissue repair and regeneration. But hh signaling has a second—much darker—face: it plays an important role in several types of human cancers where it promotes growth and enables proliferation of tumor stem cells. The etiology of medulloblastoma and basal cell carcinoma is tightly linked to aberrant hh activity, but also cancers of the prostate, the pancreas, the colon, the breasts, rhabdomyosarcoma, and leukemia, are dependent on irregular hh activity. Recent clinical studies have shown that hh signaling can be the basis of an important new class of therapeutic agents with far-reaching implications in oncology. Thus, modulation of hh signaling by means of small molecules has emerged as a valuable tool in combating these hh-dependent cancers. Cyclopamine, a unique natural product with a fascinating history, was the first identified inhibitor of hh signaling and its story is closely linked to the progress in the whole field. In this review we will trace the story of cyclopamine, give an overview on the biological modes of hh signaling both in untransformed and malignant cells, and finally present potent modulators of the hh pathway—many of them already in clinical studies. For more than 30 years now the knowledge on hh signaling has grown steadily—an end to this development is far from being conceivable.

6. Cyclopamine and Hedgehog-Signaling: Chemistry, Biology, Medical Perspectives

P. Heretsch, L. Tzagkaroulaki, A. Giannis

Angew. Chem. Int. Ed. 2010, 49, 3418-3427; Angew. Chem. 2010, 122, 3492-3502

http://onlinelibrary.wiley.com/doi/10.10 ...http://onlinelibrary.wiley.com/doi/10.10 ...

When Odysseus left the devastated city of Troy after ten years of siege he could not foresee the perils he still had to face. The encounter with the cyclops, a giant with only one eye placed in the middle of its forehead, was doubtlessly one of the creepiest and most dangerous of his adventures. In the end, Odysseus could only escape with the help of a sheep. Whether Homers cyclops was inspired by the observation of terribly malformed neonates remains speculative. However, when sheep herders in Idaho in the middle of the 20th century faced an increasing number of cyclops-like sheep in their herds, a unique cascade of chemical, biological, and medicinal discoveries was initiated. This Minireview tells this story and shows its impact on modern biomedical research.

5. A Biomimetic Approach to C-nor-D-homo-Steroids

P. Heretsch, S. Rabe, A. Giannis

J. Am. Chem. Soc. 2010, 132, 9968-9969

http://pubs.acs.org/doi/abs/10.1021/ja10 ...

A biomimetic three-step transformation of classical “6-6-6-5”-steroids into their C-nor-D-homo-counterparts gives an easy and fast access to this highly important substructure of natural products, as it is found in cyclopamine, and nakiterpiosin. A novel reagent combination allows for the rearrangement even of 17-keto steroids with high endoselectivity. In several examples the broadness of this strategy is outlined.

4. Synthesis of All Diastereomers of the Piperidine-Alkaloid-Substructure of Cyclopamine

P. Heretsch, S. Rabe, A. Giannis

Org. Lett. 2009, 11, 5410-5412

http://pubs.acs.org/doi/abs/10.1021/ol90 ...

All four diastereomers of the trisubstituted piperidine−alkaloids of the veratramine and jervine type were synthesized with complete stereocontrol starting from enantiopure citronellic acids. The flexible, high-yielding, and scalable route described here will facilitate convergent syntheses and give access to analogues of cyclopamine and other biologically active and diverse steroid alkaloids.

3. Synthesis of Cyclopamine Using a Biomimetic and Diastereoselective Approach

A. Giannis, P. Heretsch, V. Sarli, A. Stößel

Angew. Chem. Int. Ed. 2009, 48, 7911-7914; Angew. Chem. 2009, 121, 8052-8055

http://onlinelibrary.wiley.com/doi/10.10 ...http://onlinelibrary.wiley.com/doi/10.10 ...

Cyclopamine, the first inhibitor of the hedgehog signaling pathway, causes cyclopia in embryos but in adults it is a potent anticancer drug. A concise biomimetic and diastereoselective synthesis of cyclopamine (2) starting from commercially available dehydroepiandrosterone (1) now also provides access to several analogues.

2. Syntheses with a Chiral Building Block from the Citric Acid Cycle: (2R,3S)-Isocitric Acid by Fermentation of Sunflower Oil

P. Heretsch, F. Thomas, A. Aurich, H. Krautscheid, D. Sicker, A. Giannis

Angew. Chem. Int. Ed. 2008, 47, 1958-1960; Angew. Chem. 2008, 120, 1984-1986

http://onlinelibrary.wiley.com/doi/10.10 ...http://onlinelibrary.wiley.com/doi/10.10 ...

Previously, (2R,3S)-isocitric acid (1), a component of the citric acid cycle, had not been available on a preparative scale. A new route to this acid on a kilogram scale combines a biotechnological formation through fermentation from sunflower oil with a chemical separation process. In a variety of transformations into further chiral derivatives, 1 is established as a valuable new member of the chiral pool (see scheme).

1. An Efficient Entry to Amino-Substituted Resorcylic Acid Derivatives for the Synthesis of Platensimycin and Analogues

P. Heretsch, A. Giannis

Synthesis 2007, 17, 2614-2616

https://www.thieme-connect.com/products/ ...

An efficient entry to protected amino-substituted resorcylic acid derivatives, methyl 3- or 5-amino-2,4-bis(methoxy­methoxy)benzoate, is reported. Both derivatives can be used for the synthesis of platensimycin and its analogues.