ABSTRACT
A series of novel vindoline-piperazine conjugates were synthesized by coupling 6 N-substituted piperazine pharmacophores at positions 10 and 17 of Vinca alkaloid monomer vindoline through different types of linkers. The in vitro antiproliferative activity of the 17 new conjugates was investigated on 60 human tumor cell lines (NCI60). Nine compounds presented significant antiproliferative effects. The most potent derivatives showed low micromolar growth inhibition (GI50) values against most of the cell lines. Among them, conjugates containing [4-(trifluoromethyl)benzyl]piperazine (23) and 1-bis(4-fluorophenyl)methyl piperazine (25) in position 17 of vindoline were outstanding. The first one was the most effective on the breast cancer MDA-MB-468 cell line (GI50 = 1.00 µM), while the second one was the most effective on the non-small cell lung cancer cell line HOP-92 (GI50 = 1.35 µM). The CellTiter-Glo Luminescent Cell Viability Assay was performed with conjugates 20, 23, and 25 on non-tumor Chinese hamster ovary (CHO) cells to determine the selectivity of the conjugates for cancer cells. These compounds exhibited promising selectivity with estimated half-maximal inhibitory concentration (IC50) values of 2.54 µM, 10.8 µM, and 6.64 µM, respectively. The obtained results may have an impact on the design of novel vindoline-based anticancer compounds.
Subject(s)
Antineoplastic Agents , Cell Proliferation , Cricetulus , Piperazine , Piperazines , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , CHO Cells , Animals , Piperazines/pharmacology , Piperazines/chemistry , Piperazines/chemical synthesis , Cell Proliferation/drug effects , Piperazine/chemistry , Piperazine/pharmacology , Vinblastine/analogs & derivatives , Vinblastine/pharmacology , Vinblastine/chemistry , Vinblastine/chemical synthesis , Drug Screening Assays, Antitumor , Structure-Activity Relationship , Cell Survival/drug effectsABSTRACT
In the frame of our diversity-oriented research on multitarget small molecule anticancer agents, utilizing convergent synthetic sequences terminated by Sonogashira coupling reactions, a preliminary selection of representative alkyne-tethered vindoline hybrids was synthesized. The novel hybrids with additional pharmacophoric fragments of well-documented anticancer agents, including FDA-approved tyrosine-kinase inhibitors (imatinib and erlotinib) or ferrocene or chalcone units, were evaluated for their antiproliferative activity on malignant cell lines MDA-MB-231 (triple negative breast cancer), A2780 (ovarian cancer), HeLa (human cervical cancer), and SH-SY5Y (neuroblastoma) as well as on human embryonal lung fibroblast cell line MRC-5, which served as a reference non-malignant cell line for the assessment of the therapeutic window of the tested hybrids. The biological assays identified a trimethoxyphenyl-containing chalcone-vindoline hybrid (36) as a promising lead compound exhibiting submicromolar activity on A2780 cells with a marked therapeutic window.
Subject(s)
Alkynes , Antineoplastic Agents , Cell Proliferation , Vinblastine , Humans , Cell Proliferation/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Alkynes/chemistry , Alkynes/pharmacology , Cell Line, Tumor , Vinblastine/pharmacology , Vinblastine/analogs & derivatives , Vinblastine/chemistry , Vinblastine/chemical synthesis , Drug Screening Assays, Antitumor , HeLa Cells , Structure-Activity RelationshipABSTRACT
A new triarylaminium radical cation promoted coupling of catharanthine with vindoline is disclosed, enlisting tris(4-bromophenyl)aminium hexachlororantimonate (BAHA, 1.1 equiv) in aqueous 0.05 N HCl/trifluoroethanol (1-10:1) at room temperature (25 °C), that provides anhydrovinblastine in superb yield (85%) with complete control of the newly formed quaternary C16' stereochemistry. A definition of the scope of aromatic substrates that participate with catharanthine in the BAHA-mediated diastereoselective coupling reaction and simplified indole substrates other than catharanthine that participate in the reaction are disclosed that identify the key structural features required for participation in the reaction, providing a generalized indole functionalization reaction that bears little structural relationship to catharanthine or vindoline.
Subject(s)
Amines/chemistry , Vinblastine/analogs & derivatives , Vinblastine/chemical synthesis , Vinca Alkaloids/chemistry , Cations/chemistry , Free Radicals/chemistry , Molecular Structure , Stereoisomerism , Vinblastine/chemistryABSTRACT
We achieved direct construction of the common pyrrolo[2,3-d]carbazole core of aspidosperma and malagasy alkaloids by a gold-catalyzed cascade cyclization of ynamide. This reaction involves intramolecular cyclization from indole to ynamide followed by trapping of the resulting iminium intermediate. Through the use of chiral gold complexes, an enantiomerically enriched pyrrolo[2,3-d]carbazole was obtained in up to 74% ee. This methodology was successfully applied to the asymmetric formal synthesis of vindorosine.
Subject(s)
Alkaloids/chemical synthesis , Gold , Spiro Compounds/chemistry , Vinblastine/analogs & derivatives , Alkaloids/chemistry , Catalysis , Models, Molecular , Molecular Structure , Vinblastine/chemical synthesisABSTRACT
BACKGROUND: Vinorelbine bitartrate (VRL) is an antimitotic agent approved by FDA for breast cancer and non-small cell lung cancer (NSCLC) in many countries. However, high aqueous solubility and thermo degradable nature of VRL limited the availability of marketed dosage forms. OBJECTIVES: The current work is focused on the development of lipid based aqueous core nanocapsules which can encapsulate the hydrophilic VRL in the aqueous core of nanocapsules protected with a lipidic shell which will further provide a sustained release. METHODS: The ACNs were prepared by double emulsification technique followed by solvent evaporation. Box Behnken Design was utilized to optimize the formulation and process variables. Thirteen batches were generated utilizing lipid concentration, surfactant concentration and homogenizer speed as dependent variables (at three levels) and particle size and encapsulation efficiency as critical quality attributes. The ACNs were characterized for particle size, zeta potential, polydispersity index (PDI), entrapment efficiency, morphology by Transmission Electron Microscopy (TEM) and in vitro release. The ACNs were further evaluated for safety against intravenous administration by haemocompatibility studies. RESULTS: Results demonstrated that lipidic nanocapsules enhanced the entrapment efficiency of VRL up to 78%. Transmission Electron Microscopy revealed spherical shape of ACNs with core-shell structure. The GMS-VRL-ACNs showed that release followed Korsemeyer peppas kinetics suggesting Fickian diffusion. Moreover, the compliance towards haemocompatibility studies depicted the safety of prepared nanocapsules against intravenous administration. CONCLUSION: ACNs were found to be promising in encapsulating high aqueous soluble anticancer drugs with enhanced entrapment and safety towards intravenous administration.
Subject(s)
Lipids/chemistry , Nanocapsules/chemistry , Tartrates/chemistry , Vinblastine/chemistry , Administration, Intravenous , Diffusion , Humans , Hydrophobic and Hydrophilic Interactions , Particle Size , Surface Properties , Tartrates/administration & dosage , Tartrates/chemical synthesis , Vinblastine/administration & dosage , Vinblastine/chemical synthesis , Water/chemistryABSTRACT
A series of 180 vinblastine 20' amides were prepared in three steps from commercially available starting materials, systematically exploring a typically inaccessible site in the molecule enlisting a powerful functionalization strategy. Clear structure-activity relationships and a structural model were developed in the studies which provided many such 20' amides that exhibit substantial and some even remarkable enhancements in potency, many that exhibit further improvements in activity against a Pgp overexpressing resistant cancer cell line, and an important subset of the vinblastine analogues that display little or no differential in activity against a matched pair of vinblastine sensitive and resistant (Pgp overexpressing) cell lines. The improvements in potency directly correlated with target tubulin binding affinity, and the reduction in differential functional activity against the sensitive and Pgp overexpressing resistant cell lines was found to correlate directly with an impact on Pgp-derived efflux.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm , Neoplasms/drug therapy , Vinblastine/analogs & derivatives , Vinblastine/pharmacology , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Drug Resistance, Multiple , Humans , Neoplasms/metabolism , Structure-Activity Relationship , Tubulin/metabolism , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacology , Vinblastine/chemical synthesisABSTRACT
A key series of vinblastine analogs 7-13, which contain modifications to the C20' ethyl group, was prepared with use of two distinct synthetic approaches that provide modifications of the C20' side chain containing linear and cyclized alkyl groups or added functionalized substituents. Their examination revealed the unique nature of the improved properties of the synthetic vinblastine 6, offers insights into the origins of its increased tubulin binding affinity and 10-fold improved cell growth inhibition potency, and served to probe a small hydrophobic pocket anchoring the binding of vinblastine with tubulin. Especially noteworthy were the trends observed with substitution of the terminal carbon of the ethyl group that, with the exception of 9 (R=F vs H, equipotent), led to remarkably substantial reductions in activity (>10-fold): R=F (equipotent with H)>N3, CN (10-fold)>Me (50-fold)>Et (100-fold)>OH (inactive). This is in sharp contrast to the maintained (7) or enhanced activity (6) observed with its incorporation into a cyclic C20'/C15'-fused six-membered ring.
Subject(s)
Antineoplastic Agents/chemistry , Vinblastine/analogs & derivatives , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Binding Sites , Crystallography, X-Ray , HCT116 Cells , Humans , Molecular Dynamics Simulation , Protein Binding/drug effects , Structure-Activity Relationship , Tubulin/chemistry , Tubulin/metabolism , Vinblastine/chemical synthesis , Vinblastine/pharmacologyABSTRACT
It is demonstrated that natural product vindoline can enhance the glucose-stimulated insulin secretion (GSIS) in MIN6 cells with the EC50 value of 50.2µM. In order to improve the activities, a series of vindoline derivatives are synthesized and evaluated in MIN6 cells. Compounds 4, 8, 17 and 24 show about 4.5 times more effective stimulation insulin secretion ability (EC50: 10.4, 14.2, 11.0 and 12.7µM, respectively) than vindoline.
Subject(s)
Glucose , Insulin-Secreting Cells/drug effects , Insulin/metabolism , Vinblastine/analogs & derivatives , Animals , Cell Line , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Inhibitory Concentration 50 , Insulin Secretion , Mice , Molecular Structure , Vinblastine/chemical synthesis , Vinblastine/chemistry , Vinblastine/pharmacologyABSTRACT
Approaches to improving the biological properties of natural products typically strive to modify their structures to identify the essential pharmacophore, or make functional group changes to improve biological target affinity or functional activity, change physical properties, enhance stability, or introduce conformational constraints. Aside from accessible semisynthetic modifications of existing functional groups, rarely does one consider using chemical synthesis to add molecular complexity to the natural product. In part, this may be attributed to the added challenge intrinsic in the synthesis of an even more complex compound. Herein, we report synthetically derived, structurally more complex vinblastines inaccessible from the natural product itself that are a stunning 100-fold more active (IC50 values, 50-75 pM vs. 7 nM; HCT116), and that are now accessible because of advances in the total synthesis of the natural product. The newly discovered ultrapotent vinblastines, which may look highly unusual upon first inspection, bind tubulin with much higher affinity and likely further disrupt the tubulin head-to-tail α/ß dimer-dimer interaction by virtue of the strategic placement of an added conformationally well-defined, rigid, and extended C20' urea along the adjacent continuing protein-protein interface. In this case, the added molecular complexity was used to markedly enhance target binding and functional biological activity (100-fold), and likely represents a general approach to improving the properties of other natural products targeting a protein-protein interaction.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Chemistry Techniques, Synthetic , Tubulin Modulators/chemical synthesis , Tubulin/chemistry , Urea/chemistry , Vinblastine/analogs & derivatives , Antineoplastic Agents, Phytogenic/pharmacology , Binding Sites , Biological Products/chemistry , Cell Line, Tumor , Drug Design , HCT116 Cells , Humans , Inhibitory Concentration 50 , Protein Binding , Protein Interaction Domains and Motifs , Protein Multimerization , Protein Structure, Secondary , Structure-Activity Relationship , Tubulin Modulators/pharmacology , Vinblastine/chemical synthesis , Vinblastine/chemistry , Vinblastine/pharmacology , Vinca Alkaloids/chemistryABSTRACT
Many natural products, including vinblastine, have not been easily subjected to simplifications in their structures by synthetic means or modifications by late-stage semisynthetic derivatization in ways that enhance their biological potency. Herein, we detail a synthetic vinblastine that incorporates added benign complexity (ABC), which improves activity 10-fold, and is now accessible as a result of advances in the total synthesis of the natural product. The compound incorporates designed added molecular complexity but no new functional groups and maintains all existing structural and conformational features of the natural product. It constitutes a member of an analogue class presently inaccessible by semisynthetic derivatization of the natural product, by its late-stage functionalization, or by biosynthetic means. Rather, it was accessed by synthetic means, using an appropriately modified powerful penultimate single-step vindoline-catharanthine coupling strategy that proceeds with a higher diastereoselectivity than found for the natural product itself.
Subject(s)
Drug Design , Vinblastine/chemistry , Vinblastine/chemical synthesis , Biological Products/chemistry , Chemistry Techniques, Synthetic , StereoisomerismABSTRACT
A summary of the development and initial studies on the scope of a powerful tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles is detailed and provides the foundation for its subsequent use in organic synthesis. Implemented with substrates in which both the initiating dienophile and subsequent dipolarophile are tethered to the 1,3,4-oxadiazoles, the studies expanded the scope of oxadiazoles that participate in the reaction cascade, permitted the use of differentiated dienophiles and dipolarophiles, extended their use to unsymmetrical dienophiles and dipolarophiles, provided exclusive control of the cycloaddition regioselectivities, and imposed exquisite control on the cycloaddition stereochemistry. As key reactivity and stereochemical features of the reactions were being defined, the cascade cycloaddition reaction was implemented in the total synthesis of a series of alkaloids including (-)-vindoline, (-)-vindorosine, the closely related natural products (+)-4-desacetoxyvindoline and (+)-4-desacetoxyvindorosine, natural minovine, (+)-N-methylaspidospermidine, (+)-spegazzinine, (-)-aspidospermine, and a number of key analogues. Most recently, it was used in the divergent total syntheses of (+)-fendleridine, (-)-kopsinine, (-)-kopsifoline D, and (-)-deoxoapodine, in which four different strategic bonds in four different classes of the hexacyclic alkaloids were formed from a common cascade cycloaddition intermediate. A large number of vindoline analogues were prepared by variations on the cascade cycloaddition reaction for single step incorporation into analogues of vinblastine. These structural changes to vindoline permitted both systematic alterations to the peripheral substituents as well as deep-seated changes to the core structure and embedded functionality of vinblastine not previously accessible. Although explored initially for accessing vindoline and vinblastine, the use of the cycloaddition cascade in the total synthesis of an impressive range of additional natural products illustrate the power of the methodology. Alternative tethering strategies for the cascade cycloaddition reaction, combined intramolecular and intermolecular variants of either the initiating Diels-Alder reaction or the subsequent carbonyl ylide 1,3-dipolar cycloaddition, an expanded examination of the tethered dipolarophile scope, and applications to additional natural product classes represent attractive areas for future work.
Subject(s)
Oxadiazoles/chemistry , Vinblastine/analogs & derivatives , Vinblastine/chemical synthesis , Cycloaddition Reaction , Molecular StructureABSTRACT
Dimeric indole alkaloids (DIAs), such as vinblastine and vincristine, found in Catharanthus roseus are used clinically as antitumor drugs. A stable supply of DIAs is desired because these alkaloids are very expensive due to their low abundance in plants. A coupling reaction between catharanthine (CAT) and vindoline (VID) is the rate-limiting step of DIAs biosynthesis in planta. 3', 4'-Anhydrovinblastine (AVLB), the product of the coupling reaction, is the precursor of CAT and VID. Therefore, an effective AVLB production system is greatly required. Previously we found that the coupling reaction of CAT and VID to produce AVLB occurred in the presence of flavin mononucleotide and manganese ion (II) by irradiation with near-ultraviolet light at a peak of 370 nm without the presence of any enzyme. In this study, we investigated the effects of organic solvents on this non-enzymatic reaction. We show that the addition of 10% methanol to the reaction mixture permitted the preparation of a highly concentrated substrate solution, resulting in a high yield of AVLB by the coupling reaction. Conditions for the coupling reaction in 10% methanol solution were optimized. We also confirmed that the coupling reaction could occur in crude extracts of C. roseus obtained by organic solvent extraction. These findings suggest a method to produce DIAs on a large scale with reduced production costs.
Subject(s)
Catharanthus/chemistry , Plant Extracts/chemistry , Ultraviolet Rays , Vinblastine/analogs & derivatives , Plant Leaves/chemistry , Vinblastine/chemical synthesisABSTRACT
It is reported that an allene dienophile can initiate a tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles, that the intermediate cross-conjugated 1,3-dipole (a carbonyl ylide) can participate in an ensuing [3 + 2] dipolar cycloaddition in a remarkably effective manner, and that the reaction can be implemented to provide the core pentacyclic ring system of vindoline. Its discovery improves a previous total synthesis of (-)-vindoline and was used in a total synthesis of (+)-4-epi-vindoline and (+)-4-epi-vinblastine that additionally enlists an alternative series of late-stage transformations.
Subject(s)
Alkadienes/chemistry , Oxadiazoles/chemistry , Vinblastine/analogs & derivatives , Cycloaddition Reaction , Molecular Structure , Stereoisomerism , Vinblastine/chemical synthesis , Vinblastine/chemistryABSTRACT
Recent publications highlighted that vinca derivatives either functionalized on C-12' or enlarged on cycle C' could be more cytotoxic than vinblastine or vinorelbine, both used in anti-cancer therapy. By combining these two results, nine new 7'-homo-anhydrovinblastine derivatives functionalized on C-13' were elaborated. The synthesis of key intermediates, their one-step transformation into final products in mild conditions and their biological activities are presented.
Subject(s)
Antineoplastic Agents/chemical synthesis , Vinblastine/analogs & derivatives , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , HCT116 Cells , Humans , K562 Cells , Tubulin/chemistry , Tubulin/metabolism , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacology , Vinblastine/chemical synthesis , Vinblastine/chemistry , Vinblastine/pharmacology , Vinca Alkaloids/chemistry , VinorelbineABSTRACT
Biologically active natural products composed of fascinatingly complex structures are often regarded as not amenable to traditional systematic structure-function studies enlisted in medicinal chemistry for the optimization of their properties beyond what might be accomplished by semisynthetic modification. Herein, we summarize our recent studies on the Vinca alkaloids vinblastine and vincristine, often considered as prototypical members of such natural products, that not only inspired the development of powerful new synthetic methodology designed to expedite their total synthesis but have subsequently led to the discovery of several distinct classes of new, more potent, and previously inaccessible analogues. With use of the newly developed methodology and in addition to ongoing efforts to systematically define the importance of each embedded structural feature of vinblastine, two classes of analogues already have been discovered that enhance the potency of the natural products >10-fold. In one instance, remarkable progress has also been made on the refractory problem of reducing Pgp transport responsible for clinical resistance with a series of derivatives made accessible only using the newly developed synthetic methodology. Unlike the removal of vinblastine structural features or substituents, which typically has a detrimental impact, the additions of new structural features have been found that can enhance target tubulin binding affinity and functional activity while simultaneously disrupting Pgp binding, transport, and functional resistance. Already analogues are in hand that are deserving of full preclinical development, and it is a tribute to the advances in organic synthesis that they are readily accessible even on a natural product of a complexity once thought refractory to such an approach.
Subject(s)
Biological Products/chemical synthesis , Biological Products/pharmacology , Vinblastine , Animals , Biological Products/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Models, Molecular , Molecular Conformation , Structure-Activity Relationship , Vinblastine/analogs & derivatives , Vinblastine/chemical synthesis , Vinblastine/chemistry , Vinblastine/pharmacologyABSTRACT
Hybrids of vinca alkaloids and phomopsin A have been elaborated with the aim of interfering with the "vinca site" and the "peptide site" of the vinca domain in tubulin. They were synthesized by an efficient one-pot procedure that directly links the octahydrophomopsin lateral chain to the velbenamine moiety of 7'-homo-anhydrovinblastine. In their modeled complexes with tubulin, these hybrids were found to superimpose nicely on the tubulin-bound structures of vinblastine and phomopsin A. This good matching can account for the fact that two of them are very potent inhibitors of microtubules assembly and are cytotoxic against four cancer cell lines.
Subject(s)
Antineoplastic Agents/chemical synthesis , Mycotoxins/chemical synthesis , Vinblastine/analogs & derivatives , Vinblastine/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Mycotoxins/chemistry , Mycotoxins/pharmacology , Tubulin/chemistry , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacology , Vinblastine/chemistry , Vinblastine/pharmacologyABSTRACT
A powerful tandem [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles initiated by a transannular [4 + 2] cycloaddition is detailed. An impressive four rings, four carbon-carbon bonds, and six stereocenters are set on each site of the newly formed central six-membered ring in a cascade thermal reaction that proceeds at temperatures as low as 80 °C. The resulting cycloadducts provide the basis for the synthesis of unique analogues of vinblastine containing metabolically benign deep-seated cyclic modifications at the C3/C4 centers of the vindoline-derived subunit of the natural product.
Subject(s)
Oxadiazoles/chemistry , Vinblastine/chemical synthesis , Cyclization , Molecular Structure , Stereoisomerism , Vinblastine/chemistryABSTRACT
The syntheses of 20,20-difluorocatharanthine and congeners, starting from the naturally occurring catharanthine, are reported. The fluorinated catharanthine analogues were investigated as potential precursors to dimeric Vinca alkaloids of the vinflunine family. However, the biomimetic coupling of the fluorinated catharanthine derivatives with vindoline led to unexpected alkaloid structures, the formation of which was rationalized.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Catharanthus/chemistry , Vinblastine/analogs & derivatives , Vinca Alkaloids/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Biomimetics/methods , Halogenation , Vinblastine/chemical synthesis , Vinblastine/chemistry , Vinca Alkaloids/chemistryABSTRACT
Sixteen new 7'-homo-anhydrovinblastine derivatives were prepared in one or two steps from vinorelbine by means of an original and regiospecific rearrangement and subsequent diastereoselective reduction. This strategy has allowed fast access to a family of vinca alkaloid derivatives with an enlarged and functionalized ring C'. Their synthesis and biological evaluation are reported. One compound (compound 35) is 1.7 times more active than vinorelbine as a tubulin assembly inhibitor. Moreover, some of these compounds are highly cytotoxic, and two of them are more potent than vinorelbine on HCT116 and K562 cell lines. Molecular modeling studies, carried out with two of the new vinca derivatives, provide useful hints about how a given functionalization introduced at positions 7' and 8' of the C' ring results in improved binding interactions between one of the new derivatives and the interdimer interface when compared to the parent compound vinblastine.
Subject(s)
Antineoplastic Agents/chemical synthesis , Tubulin Modulators/chemical synthesis , Vinblastine/analogs & derivatives , Vinblastine/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Microtubules/chemistry , Models, Molecular , Stereoisomerism , Structure-Activity Relationship , Tubulin Modulators/pharmacology , Vinblastine/pharmacologyABSTRACT
The total synthesis of a systematic series of vinblastine analogues that contain deep-seated structural modifications to the core ring system of the lower vindoline subunit is described. Complementary to the vindoline 6,5 DE ring system, compounds with 5,5, 6,6, and the reversed 5,6 membered DE ring systems were prepared. Both the natural cis and unnatural trans 6,6-membered ring systems proved accessible, with the latter representing a surprisingly effective class for analogue design. Following Fe(III)-promoted coupling with catharanthine and in situ oxidation to provide the corresponding vinblastine analogues, their evaluation provided unanticipated insights into how the structure of the vindoline subunit contributes to activity. Two potent analogues (81 and 44) possessing two different unprecedented modifications to the vindoline subunit core architecture were discovered that matched the potency of the comparison natural products and both lack the 6,7-double bond whose removal in vinblastine leads to a 100-fold drop in activity.