Cryptophycin unit B analogues

• Thomas Schachtsiek,
• Jona Voss,
• Maren Hamsen,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2025, 21, 526–532, doi:10.3762/bjoc.21.40

• ongoing challenge. Cryptophycins are a class of cyclic depsipeptides renowned for their high cytotoxicity in the picomolar range often combined with efficacy against multidrug-resistant tumour cell lines. However, cryptophycins failed as stand-alone drugs in cancer treatment, and their naturally occurring

• derivatives lack a covalent attachment handle. By making use of drug conjugates, toxic payloads such as cryptophycins can be selectively delivered to the target site. We present the synthesis of two conjugable cryptophycins with amino groups in unit B, representing potential payloads for drug conjugates

• particularly effective against multidrug-resistant cancers. Keywords: cancer treatment; cryptophycins; drug conjugates; payload; targeted delivery; Introduction Cryptophycins emerged as highly potent cytotoxins for the use in targeted cancer therapy [1]. Originally discovered over three decades ago by

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• demonstrated that some of them exhibit comparable activities to the clinically approved antibiotics against Gram-positive strains while also enhancing activities against Gram-negative pathogens. The cryptophycins The cryptophycins are a large family of 16-membered ring depsipeptide natural products, which

• exhibit a potent ability to induce tubulin depolymerization [77], originally isolated from the cyanobacteria Nostoc sp. ATCC 53789 [78]. Notably, the cryptophycins cannot serve as substrates for P-glycoprotein and multiple drug resistance-associated proteins, making them attractive as chemotherapeutic

• cryptophycins. Funding This work is financially supported by the National Natural Science Foundation of China (22301041), the Natural Science Foundation of Shanghai Municipality (23ZR1412900), and the start-up funding of Fudan University.

Novel unit B cryptophycin analogues as payloads for targeted therapy

• Eduard Figueras,
• Adina Borbély,
• Mohamed Ismail,
• Marcel Frese and
• Norbert Sewald

Beilstein J. Org. Chem. 2018, 14, 1281–1286, doi:10.3762/bjoc.14.109

• Eduard Figueras Adina Borbely Mohamed Ismail Marcel Frese Norbert Sewald Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstraße 25, 33615 Bielefeld, Germany 10.3762/bjoc.14.109 Abstract Cryptophycins are naturally occurring cytotoxins with great

• Cryptophycins are natural occurring cyclic depsipeptides that were first isolated from cyanobacteria Nostoc sp. ATCC 53789 in 1990 [1]. Cryptophycins target tubulin, in particular the peptide site of the vinca domain. They block microtubule formation, inhibiting their assembly and, hence, are antimitotic agents

• modified unit B (13 or 14), affording the according linear cryptophycins 18 and 19 in acceptable yields (51–59%). Compounds 18 and 19 were treated with trifluoroacetic acid for simultaneous Boc and t-Bu removal, which also cleaved the dioxolane ring. Subsequently, macrolactamization was performed under

Total synthesis and biological evaluation of fluorinated cryptophycins

• Christine Weiß,
• Tobias Bogner,
• Benedikt Sammet and
• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 2060–2066, doi:10.3762/bjoc.8.231

• Christine Weiss Tobias Bogner Benedikt Sammet Norbert Sewald Organic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, PO Box 100131, 33501 Bielefeld, Germany 10.3762/bjoc.8.231 Abstract Cryptophycins are cytotoxic natural products that exhibit considerable activities even

• against multi-drug-resistant tumor cell lines. As fluorinated pharmaceuticals have become more and more important during the past decades, fluorine-functionalized cryptophycins were synthesized and evaluated in cell-based cytotoxicity assays. The unit A trifluoromethyl-modified cryptophycin proved to be

• ; fluorinated natural product analogues; structure-activity relationship; Introduction Cryptophycins form a class of cytotoxic sixteen-membered macrocyclic depsipeptides. Cryptophycin-1 (1) was isolated for the first time in 1990 from cyanobacteria Nostoc sp. ATCC 53789 [1] (Figure 1). Moore et al. isolated

Natural product biosyntheses in cyanobacteria: A treasure trove of unique enzymes

• Jan-Christoph Kehr,
• Douglas Gatte Picchi and
• Elke Dittmann

Beilstein J. Org. Chem. 2011, 7, 1622–1635, doi:10.3762/bjoc.7.191

• -tail linkage [56]. Cryptophycin Cryptophycins were shown to be produced by terrestrial strains of Nostoc that are either free living or associated with a lichen symbiont. Cryptophycin 1 (15) is the most potent tubulin-destabilizing compound ever discovered and serves as a leading product for the

A two step synthesis of a key unit B precursor of cryptophycins by asymmetric hydrogenation

• Benedikt Sammet,
• Mathilde Brax and
• Norbert Sewald

Beilstein J. Org. Chem. 2011, 7, 243–245, doi:10.3762/bjoc.7.32

• Benedikt Sammet Mathilde Brax Norbert Sewald Bielefeld University, Department of Chemistry, Organic and Bioorganic Chemistry, Universitätsstraße 25, 33615 Bielefeld, Germany 10.3762/bjoc.7.32 Abstract A novel highly enantioselective two step access to a unit B precursor of cryptophycins in good

• enantioselectivity, and avoids hazardous reaction conditions. Keywords: amino acid; asymmetric hydrogenation; cryptophycin; DuPhos; Introduction Cryptophycins are macrocyclic depsipeptides, which show very high cytotoxicity even against multidrug-resistant cell lines. They inhibit mitosis of eukaryotic cells by

• interacting with the β-subunit of α/β-tubulin heterodimers. Numerous natural and artificial analogs have been analysed in structure–activity relationship (SAR) studies. The unit B of cryptophycins contains a considerably modified D-tyrosine derivative (Figure 1). Substituent variations at unit B are not well

Colchitaxel, a coupled compound made from microtubule inhibitors colchicine and paclitaxel

• Karunananda Bombuwala,
• Thomas Kinstle,
• Vladimir Popik,
• Sonal O. Uppal,
• James B. Olesen,
• Jose Viña and
• Carol A. Heckman

Beilstein J. Org. Chem. 2006, 2, No. 13, doi:10.1186/1860-5397-2-13

• interest has been focused on new, highly-active classes of natural products such as the dolastatins and the cryptophycins. Such natural compounds and their synthetic derivatives have been evaluated for dosage and side effects in preliminary clinical trials [12][13][14][15], but the results do not suggest