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This research investigates the potential of bioactive compounds derived from cyanobacteria as inhibitors of alphaamylase and beta-glucosidase enzymes, which are involved in starch digestion and glucose release. The study reveals strong molecular interactions between these compounds and the enzyme active sites through docking analysis. Notably, compounds such as Abietic, Anilide, Nostocarboline, Noscomin, Tanikolide, Tubercidin, Cryptophycin, and Cyanobacteria exhibit the lowest binding energies when interacting with alpha-amylase. Among them, Noscomin demonstrates the lowest docking score and binding energy against alpha-amylase, outperforming the reference compound metformin. Similarly, these compounds also display low binding energies when interacting with beta-glucosidase. The bioactive compounds from cyanobacteria show significant potential as inhibitors of alpha-amylase and beta-glucosidase, suggesting their efficacy in managing diabetes by slowing down starch digestion and controlling glucose release. Their superior binding affinities and lower binding energies, particularly Noscomin, indicate their potential in regulating blood sugar levels by interacting effectively with these enzymes. Thus, these compounds hold promise as valuable leads for developing alpha-amylase and beta-glucosidase inhibitors, contributing to the management of diabetes. Further research is required to understand the underlying mechanisms of action and assess the bioavailability, toxicity, and pharmacological potential of these cyanobacterial compounds. This investigation provides valuable insights into the potential of cyanobacterial bioactive compounds as effective candidates for the development of novel therapeutics targeting alphaamylase and beta-glucosidase enzymes in diabetes management. [ABSTRACT FROM AUTHOR]

Cryptophycins are microtubule-targeting agents (MTAs) that belong to the most potent antimitotic compounds known to date; however, their exact molecular mechanism of action remains unclear. Here, we present the 2.2 Å resolution X-ray crystal structure of a potent cryptophycin derivative bound to the αβ-tubulin heterodimer. The structure addresses conformational issues present in a previous 3.3 Å resolution cryo-electron microscopy structure of cryptophycin-52 bound to the maytansine site of β-tubulin. It further provides atomic details on interactions of cryptophycins, which had not been described previously, including ones that are in line with structure-activity relationship studies. Interestingly, we discovered a second cryptophycin-binding site that involves the T5-loop of β-tubulin, a critical secondary structure element involved in the exchange of the guanosine nucleotide and in the formation of longitudinal tubulin contacts in microtubules. Cryptophycins are the first natural ligands found to bind to this new "βT5-loop site" that bridges the maytansine and vinca sites. Our results offer unique avenues to rationally design novel MTAs with the capacity to modulate T5-loop dynamics and to simultaneously engage multiple β-tubulin binding sites., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Tubulin binding compounds represent one of the most attractive targets for anticancer drug development. They broadly fall into two categories viz., tubulin polymerization inhibitors, which block microtubule growth and destabilize microtubules like vinca alkaloids and cryptophycins, and the others, which polymerize microtubules into hyperstable forms represented by family of taxanes. In this context, we aimed at design and synthesis of cryptophycins based macrocyclic depsipeptides, which are synthetically more accessible, however have the basic information to target tubulins and establish structure activity relationship (SAR). Thus, a new class of cryptophycins based marocyclic depsipeptides with a truncated epoxide chain were synthesized as potential tubulin inhibitors. The resultant lead analogues 15a and 16a exhibited good anti-cancer activity, induced apoptosis, caused block/delay in cell cycle as well as significantly reduced the expression of α- and β-tubulins. Molecular modelling studies show that 15a and 16a bind in the same domain as that of cryptophycins. [ABSTRACT FROM AUTHOR]

The cryptophycins are a potent class of cytotoxic agents that were evaluated as antibody drug conjugate (ADC) payloads. Free cryptophycin analog 1 displayed cell activity an order of magnitude more potent than approved ADC payloads MMAE and DM1. This potency increase was also reflected in the activity of the cryptophycin ADCs, attached via a either cleavable or non-cleavable linker. [ABSTRACT FROM AUTHOR]

Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In proliferating cells, they are essential components in the division process through the formation of the mitotic spindle. As a result of these functions, tubulin and microtubules are targets for anticancer agents. Microtubule-targeting agents can be divided into two groups: microtubule-stabilizing, and microtubule-destabilizing agents. The former bind to the tubulin polymer and stabilize microtubules, while the latter bind to the tubulin dimers and destabilize microtubules. Alteration of tubulin-microtubule equilibrium determines the disruption of the mitotic spindle, halting the cell cycle at the metaphase-anaphase transition and, eventually, resulting in cell death. Clinical application of earlier microtubule inhibitors, however, unfortunately showed several limits, such as neurological and bone marrow toxicity and the emergence of drug-resistant tumor cells. Here we review several natural and synthetic microtubule-targeting agents, which showed antitumor activity and increased efficacy in comparison to traditional drugs in various preclinical and clinical studies. Cryptophycins, combretastatins, ombrabulin, soblidotin, D-24851, epothilones and discodermolide were used in clinical trials. Some of them showed antiangiogenic and antivascular activity and others showed the ability to overcome multidrug resistance, supporting their possible use in chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract: A new asymmetric synthesis of Unit A of the cryptophycins has been carried out yielding 13% of the target product over 14 steps. The key steps of the synthesis were diastereoselective hydroboration–oxidation reactions performed on the alkenyl moiety of a 1,3-dioxane derivative 8, which can be easily prepared via the Kulinkovich cyclopropanation of protected diethyl (S)-(−)-malate followed by transformation of the resulting small rings of the product 6 into the functional groups necessary for the synthesis of the target compound. [Copyright &y& Elsevier]

Covering: 2005 to 2013 Cryptophycins are a family of antimitotic depsipeptides with very high cytotoxicity even against multi-drug resistant (MDR) cancer cells. The first representative was isolated from cyanobacteria Nostoc sp. in 1990. Their bioactivity is based on their interaction with the protein tubulin. Cryptophycins were found to induce apoptosis due to inhibition of the microtubule dynamics. Consequently, cryptophycin analogues are considered as potential antitumour agents. Retrosynthetically, cryptophycins can be subdivided into four building blocks, namely units A–D, to be assembled in the total synthesis. Since the discovery of this compound class, numerous synthetic analogues have been designed for structure–activity relationship (SAR) studies. This review gives a critical overview on cryptophycins, while the main focus lies on the synthetic challenges of recently published cryptophycins, together with emerging concepts on cryptophycin bioconjugation and prodrug design. [ABSTRACT FROM AUTHOR]

Abstract: A stereoselective synthesis of fragment A of cryptophycin is achieved utilizing the versatile Prins cyclization. Subsequently, the total synthesis of cryptophycin-24 (arenastatin A) has been accomplished by coupling it with the depsipeptide subunit. [Copyright &y& Elsevier]

Cryptophycins (Crp) are a group of cyanobacterial depsipeptides with activity against drug-resistant tumors. Although they have been shown to be promising, further efforts are required to return these highly potent compounds to the clinic through a new generation of analogues with improved medicinal properties. Herein, we report a chemosynthetic route relying on the multifunctional enzyme CrpD-M2 that incorporates a 2-hydroxy acid moiety (unit D) into Crp analogues. CrpD-M2 is a unique non-ribosomal peptide synthetase (NRPS) module comprised of condensation-adenylation-ketoreduction-thiolation (C-A-KR-T) domains. We interrogated A-domain 2-keto and 2-hydroxy acid activation and loading, and KR domain activity in the presence of NADPH and NADH. The resulting 2-hydroxy acid was elongated with three synthetic Crp chain elongation intermediate analogues through ester bond formation catalyzed by CrpD-M2 C domain. Finally, the enzyme-bound seco-Crp products were macrolactonized by the Crp thioesterase. Analysis of these sequential steps was enabled through LC-FTICR-MS of enzyme-bound intermediates and products. This novel chemoenzymatic synthesis of Crp involves four sequential catalytic steps leading to the incorporation of a 2-hydroxy acid moiety in the final chain elongation intermediate. The presented work constitutes the first example where a NRPS-embedded KR domain is employed for assembly of a fully elaborated natural product, and serves as a proof-of-principle for chemoenzymatic of new Crp analogues. [ABSTRACT FROM AUTHOR]

Unit A of cryptophycins is a δ-hydroxy acid with two or four stereogenic centers. The first synthesis of the unit A building block of cryptophycin-39 is based on a catalytic asymmetric Shi epoxidation of trans-styryl acetic acid followed by an in situ lactonization. The scope of this reaction has been investigated with respect to various β,γ-unsaturated carboxylic acids as substrates for the asymmetric synthesis of 4-hydroxy-5-phenyl-tetrahydrofuran-2-ones under Shi conditions. [ABSTRACT FROM AUTHOR]

Unit A of cryptophycins is a ?-hydroxy acid with two or four stereogenic centers. The first synthesis of the unit A building block of cryptophycin-39 is based on a catalytic asymmetric Shi epoxidation of TRANS-styryl acetic acid followed by an in situ lactonization. The scope of this reaction has been investigated with respect to various ?,?-unsaturated carboxylic acids as substrates for the asymmetric synthesis of 4-hydroxy-5-phenyl-tetrahydrofuran-2-ones under Shi conditions. [ABSTRACT FROM AUTHOR]

Cryptophycins are potent anticancer agents isolated from Nostoc sp. ATCC 53789 and Nostoc sp. GSV 224. The most potent natural cryptophycin analogues retain aβ -epoxide at the C2́-C3́ position of the molecule. A P450 epoxidase encoded by crpE recently identified from the cryptophycin gene cluster was shown to install this key functional group into cryptophycin-4 (Cr-4) to produce cryptophycin-2 (Cr-2) in a regio- and stereospecific manner. Here we report a detailed characterization of the CrpE epoxidase using an engineered maltose binding protein (MBP)-CrpE fusion. The substrate tolerance of the CrpE polypeptide was investigated with a series of structurally related cryptophycin analogues generated by chemoenzymatic synthesis. The enzyme specifically installed a β-epoxide between C2́ and C3́ of cyclic cryptophycin analogues. The k cat/Km values of the enzyme were determined to provide further insights into the P450 epoxidase catalytic efficiency affected by substrate structural variation. Finally, binding analysis revealed cooperativity of MBP-CrpE toward natural and unnatural desepoxy cryptophycin substrates. [ABSTRACT FROM AUTHOR]

Unit A of cryptophycin 1 is a δ-hydroxy acid with four stereogenic centres. Our unit A synthesis introduces the first two stereogenic centres by a catalytic, asymmetric dihydroxylation, whereas the remaining two stereogenic centres are established by diastereoselective reactions. In this letter, we focus on the diaste�reoselectivity of these reactions and discuss the accessibility of cryptophycin unit A diastereomers. [ABSTRACT FROM AUTHOR]

The enzyme kinetics of the glutathione (GSH) conjugation of cryptophycin 52 (C52, R -stereoisomer) and cryptophycin 53 (C53,   S -stereoisomer) by cytosolic glutathione S -transferases (cGSTs) from human, rat, mouse, dog and monkey liver were studied. V max , K m , and CL int values for glutathione conjugation of C52 ( R -stereoisomer) were 0.10  ±  0.01  nmol  min -1   mg -1 , 3.24  ±  0.23  µM, and (3.15  ±  0.09)  ×  10 -2   ml  min -1   mg -1 , respectively, in human cytosol. Due to limited solubility relative to the K m , only CL int values were determined in rat ((7.76  ±  0.10)  ×  10 -2   ml  min -1   mg -1 ) and mouse ((7.61  ±  0.50)  ×  10 -2   ml  min -1   mg -1 ) cytosol. Enzyme kinetic parameters could not be determined for C53 ( S -stereoisomer). Microsomal GSH conjugation in human, rat, and mouse was attributed to cytosolic contamination. No GSH conjugation was seen in any biological matrix from dog or monkey. There was little GSH conjugation of C53 by cytosol or microsomes from any species. The metabolism of C52 and C53 by epoxide hydrolase was also investigated. No diol product was observed in any biological matrix from any species. Thus, cGSTs are primarily responsible for C52 metabolism. [ABSTRACT FROM AUTHOR]

Cryptophycins, depsipeptides isolated from terrestrial blue–green algae, show potent activity against a variety of tumor cell lines. Given the potential of the cryptophycins for cancer therapy, we developed a new class of non-peptide peptidomimetic, designed to replace the 16-membered macrolide ring with a 7-membered azepine ring for attachment of the cryptophycin side chains with the required spatial orientation to mimic the conformation of the relevant region of the natural product. Monte Carlo conformational analysis revealed excellent overlay of the local minimum structural model 6 and X-ray structure of (+)-cryptophycin-3 (5). Starting from this structural model, we designed and synthesized compounds (+)-25, (+)-30, and (+)-34 as potential mimics of cryptophycins. Compounds (+)-25, (+)-30, and (+)-34 were tested for in vitro cytotoxicity against six human cancer cell lines. Although only modest activities were observed, these results suggested that a new series of bioactive cryptophycin analogues might be available by structural modification of the central ring system of the cryptophycins. [Copyright &y& Elsevier]

Purpose. To compare the pharmacokinetics and tissue distribution (both normal and tumor) of cryptophycin 52 (C-52) and its putative chlorohydrin prodrug cryptophycin 55 (C-55) in a murine model and to investigate a possible mechanism behind the superior activity of C-55. Methods. Mammary adenocarcinoma 16/c tumor-bearing mice were treated with an i.v. bolus of 11 mg/kg C-52 or 38 mg/kg C-55 in Cremophor-alcohol. At predetermined time intervals, C-52 and C-55 concentrations in plasma, liver, kidney, small intestine and tumors were measured using a previously described HPLC method. Pharmacokinetic parameters were computed using noncompartmental methods. Tissue (both normal and tumor) to plasma ratios as a function of time were also calculated for comparison. Results. Both C-52 and C-55 were rapidly distributed into different tissues including tumors following i.v. administration. However, the affinities of these compounds towards different tissues were different. Thus, the half-lives (minutes) of C-55 were in the decreasing order liver (725), intestine (494), tumor (206), kidney (62) and plasma (44), whereas the AUC values (μg·min/ml) were in the order tumor (9077), liver (7734), kidney (6790), plasma (2372) and intestine (2234). For C-52, the half-lives (minutes) were in the decreasing order liver (1333), kidney (718), intestine (389), tumor (181) and plasma (35), and the AUC values (μg·min/ml) were in the order kidney (1164), liver (609), intestine (487), plasma (457) and tumor (442). The relative exposures to C-52 after i.v. injection of C-55 were plasma 3.9%, tumor 80.8%, kidney 3.4%, liver 1.1% and intestine 2.8%. Although plasma exposure to C-52 following C-55 administration was relatively small, the use of C-55 to deliver C-52 increased the retention of C-52 and its AUC in tumor compared to direct injection of C-52. Simultaneously, this approach shortened C-52 retention in all normal tissues studied. Conclusions. The distribution of C-55 and its bioconversion to C-52 in different organs and tumor tissue observed in this study suggest the ability of C-55 to target tumor tissue, creating a depot of C-52 in tumor. Increased C-52 exposure of tumor, with concomitant decreased exposure of normal tissue, is a contributing factor to the superior activity of C-55 versus C-52. However, except in the case of tumor tissue in which 81% of C-55 converts to C-52, only a minor amount of C-55 may serve as a prodrug for C-52, whereas the majority is handled by the biosystem through a different route of elimination. Tissue distribution combined with rate of conversion may be an important determinant of the relative effectiveness of other epoxide-chlorohydrin pairs of cryptophycins. [ABSTRACT FROM AUTHOR]

An efficient synthesis of a C16 side chain benzophenone analogue of cryptophycin-24 using a crotylboration reaction and Heck coupling as key steps is described. In an in vitro tubulin assembly assay, the benzophenone analogue of the β isomer (IC50=7.4 μM) is twice as active as cryptophycin-24 (IC50=15 μM). [Copyright &y& Elsevier]

Bcl-2 has been described as a factor that can protect from apoptosis. The protective effect of Bcl-2 may be lost if the protein is phosphorylated. Bcl-2 phosphorylation can be induced by agents that affect microtubule depolymerization or prevent microtubule assembly. In 13 human tumor cell lines there was a high degree of heterogeneity in Bcl-2 protein expression. Human H460 non-small-cell lung carcinoma (NSCLC) cells expressed high levels of Bcl-2 and were selected for study. Western blot analysis for Bcl-2 phosphorylation was carried out after 4 h and 24 h of exposure to cryptophycin 52, cryptophycin 55, paclitaxel or vinblastine. Cryptophycin 52 and cryptophycin 55 were very potent inducers of Bcl-2 phosphorylation. After 4 h of exposure, Bcl-2 phosphorylation was evident with 0.05 nM cryptophycin 52, 0.25 nM cryptophycin 55, 5 nM vinblastine and 50 nM paclitaxel. The hyperphosphorylated form of Bcl-2 was evident after 24 h exposure of H460 cells to 0.25 nM cryptophycin 52 or cryptophycin 55 and 50 nM vinblastine or paclitaxel. The effects of the compounds on the cell cycle paralleled those on Bcl-2 phosphorylation. In H460 cells 90% cell killing was obtained with 0.13 nM cryptophycin 52, 0.2 nM cryptophycin 55, 20 nM paclitaxel and > 100 nM vinblastine after 24 h of exposure as determined by colony formation. In Bcl-2-negative Calu-6 NSCLC cells, 90% cell killing was obtained with 0.03 nM cryptophycin 52, 0.1 nM cryptophycin 55, 11 nM paclitaxel and 0.5 nM vinblastine using the same experimental design. Thus, cryptophycins are potent inducers of Bcl-2 phosphorylation. The cryptophycins were more potent cytotoxic agents in Bcl-2-negative Calu-6 cells than in Bcl-2-positive H460 cells indicating that pathways triggered by Bcl-2 phosphorylation are involved in cryptophycin-induced lethality. [ABSTRACT FROM AUTHOR]

Introduction/Purpose: Cryptophycins are a family of antitubulin antitumor agents. A synthetic cryptophycin derivative (LY355703, CRYPTO 52) is in early clinical evaluation. The effect of infusion time on the antitumor activity of four cryptophycins was assessed in rats bearing the 13762 mammary carcinoma and combination treatment regimens were assessed in nude mice bearing human tumor xenografts. Methods: The cryptophycins were prepared in 2% PEG300/8% cremophor/90% normal saline and delivered by jugular vein catheter on days 7, 9 and 11 post tumor implant to 13762 tumor-bearing rats. The cryptophycins prepared in the same formulation were administered by intravenous bolus injection on an alternate day schedule for five doses to human tumor xenograft bearing nude mice. Results: An infusion time of 2 h in the rats increased the tumor growth delay produced by CRYPTO 52 and CRYPTO 55, while increasing the infusion time to 6 h continued to increase the tumor growth delay for CRYPTO 292 and CRYPTO 296. Administering CRYPTO 292 at a higher dose two times was more effective than administering it at a lower dose three times. The tumor growth delays produced by the cryptophycins in the rat 13762 mammary carcinoma were greater than those with cisplatin, doxorubicin, 5-fluorouracil and 5 × 3 Gray and comparable with cyclophosphamide and gemcitabine. Combination studies were carried out in human tumor xenografts including the MX-1 breast carcinoma, the Calu-6 non-small cell lung carcinoma, the H82 small cell lung carcinoma and the SW-2 small cell lung carcinoma. CRYPTO 52 and CRYPTO 55 combined with doxorubicin, paclitaxel and 5-fluorouracil to form highly effective regimens against the human MX-1 breast carcinoma. CRYPTO 52 and CRYPTO 55 were also highly effective against the three lung carcinoma xenografts when combined with the antitumor platinum complexes, cisplatin, carboplatin or oxaliplatin. Conclusions: Cryptophycins represent a promising new class of antitumor agents that may be optimally administered by intravenous infusion and in combination with doxorubicin, paclitaxel and 5-fluorouracil. [ABSTRACT FROM AUTHOR]

Describes the convergent total synthesis of cryptophycins C and D. Absolute configuration of the alpha-amino acid; Structural assignments; Correlation of the structure of cryptophycin A to cryptophycin C.

Abstract: The aim of the present study was to predict the anticancer drug from the members of the cyanobacteria. In silico molecular docking was carried out between the cyanobacterial drug, cryptophycin-F and different types of cancer target proteins. Molecular docking also helped to compare the commercial drug, cabazitaxel with cyanobacterial drug, cryptophycin-F. The energy values produced by the cryptophycin-F with various cancer receptor molecules were ranging from −259.14 to −330.01 while, cabazitaxel showed −228.18 to −385.32. From the above results, it is concluded that cabazitaxel and cryptophycin-F produced more or less similar docking energy with cancer receptor molecules. Therefore, cryptophycin-F, a cyanobacterial drug can be employed as an alternative drug for treating various cancers without any side effects. [Copyright &y& Elsevier]

Abstract: A synthetic pathway for the synthesis of unit-B of cryptophycin-24 has been developed using Sharpless asymmetric dihydroxylation as the key step. This study shows that direct azidation of α-hydroxy acid ester using diphenylphosphoryl azide is beneficial to asymmetric synthesis of α-amino acid without the loss of chirality during the transformation. [Copyright &y& Elsevier]

Abstract: Pahayokolides A–B are cyanobacteria derived non-ribosomal peptides which exhibit cytotoxicity against a number of cancer cell lines. The biosynthetic origin of the 3-amino-2,5,7,8-tetrahydroxy-10-methylundecanoic acid (Athmu) moiety has been investigated using stable isotope incorporation experiments. While α-ketoisocaproic acid (α-KIC), α-hydroxyisocaproic acid (α-HIC), and leucine all serve as precursors to Athmu, the feeding of [1-13C] α-KIC results in more than threefold greater 13C enrichment than the other precursors. This result suggests that α-KIC is the immediate precursor which is selected and activated by the adenylation domain of the loading NRPS module and subsequently reduced in a fashion similar to that of the recently identified pathways for cryptophycins A–B, cereulide, and valinomycin. [Copyright &y& Elsevier]

An efficient total synthesis of cryptophycin-24 (arenastatin A) is reported, which features two novel synthetic strategies, the use of a RCM reaction to form the macrocycle, and the introduction of the styrene epoxide moiety prior to the macrocyclization reaction. [Copyright &y& Elsevier]

Tumor targeting has emerged as an advantageous approach to improving the efficacy and safety of cytotoxic agents or radiolabeled ligands that do not preferentially accumulate in the tumor tissue. The somatostatin receptors (SSTRs) belong to the G-protein-coupled receptor superfamily and they are overexpressed in many neuroendocrine tumors (NETs). SSTRs can be efficiently targeted with octreotide, a cyclic octapeptide that is derived from native somatostatin. The conjugation of cargoes to octreotide represents an attractive approach for effective tumor targeting. In this study, we conjugated octreotide to cryptophycin, which is a highly cytotoxic depsipeptide, through the protease cleavable Val-Cit dipeptide linker using two different self-immolative moieties. The biological activity was investigated in vitro and the self-immolative part largely influenced the stability of the conjugates. Replacement of cryptophycin by the infrared cyanine dye Cy5.5 was exploited to elucidate the tumor targeting properties of the conjugates in vitro and in vivo. The compound efficiently and selectively internalized in cells overexpressing SSTR2 and accumulated in xenografts for a prolonged time. Our results on the in vivo properties indicate that octreotide may serve as an efficient delivery vehicle for tumor targeting. [ABSTRACT FROM AUTHOR]