Bis-steroidal Pyrazine Research Articles

Performance of Green Desymmetrization Methods toward Bioactive Cephalostatin Analogues.

Since the discovery of cephalostatins, which have shown remarkable activity against human cancer cells, they have attracted the attention of researchers to target the synthesis of such impressive, complicated molecules using the green desymmetrization approach. In the current review, we report the progress in the desymmetrization of symmetrical bis-steroidal pyrazines (BSPs) as an approach toward potentially active anti-- cancer agents, namely cephalostatins/ ritterazines. The achievement of synthesizing a gram-scaled prodrug with comparable activity to the potent natural cephalostatins using green methods is our primary target. These synthetic methods can be scaled up based on the symmetrical coupling (SC) of two steroidal units of the same type. Our secondary target is the discovery of new green pathways that help in structural reconstruction programming toward the total synthesis of at least one potentially active family member. The strategy is based on functional group interconversions with high flexibility and brevity using green selective methods. The introduction of controlling groups using nontrivial reconstruction methodologies forms the backbone of our work. After certain modifications to the symmetrical BSP starting material, the resulting analogs underwent several chemoselective transformations through three main routes in rings F, D, and C. One of these routes is the chemoselective spiroketal opening (ring-F). The second route was the functionalization of the Δ14,15 bond (ring-D), including chlorination/dechlorination, in addition to epoxidation/ oxygenation processes. Finally, the introduction of the C-11 methoxy group as a directing group on ring-C led to several chemoselective transformations. Moreover, certain transformations on C-12 (ring-C), such as methylenation, followed by hydroboration- oxidation, led to a potentially active analog. The alignment of these results directs us toward the targets. Our efforts culminated in preparing effective anti-cancer prodrugs (8, 24, 30, and 31), which are able to overcome cancer drug resistance (chemoresistance) by inducing the atypical endoplasmic reticulum-mediated apoptosis pathway, which works through the release of Smac/Diablo and the activation of caspase-4.

Novel Epoxidation/Oxygenation Method toward Bioactive Cephalostatins Using Common Alkaline Metals

AbstractCephalostatins (e. g. cephalostatin 1) are a class of natural products that exert extraordinary antitumor activity with the presence of a significant number of oxygen atoms either in etheric, alcoholic, or epoxydic form. Here, we describe a novel epoxidation method of ▵14,15 bond of the symmetrical bis‐steroidal pyrazine (BSP) (the diketone 2) using only grounded lithium metal in dry THF. This chemo and regioselective method which forms an environmentally begin solved one of the major challenges that overcome the N‐oxide formation in BSP's. The epoxidized products underwent a regioselective reduction with sodium borohydride NaBH4 yielding 15α‐hydroxy derivatives. Interestingly, the triol derivative 5 was found to exert a powerful activity against the three selected cancer cell lines: K562, MCF‐7, and DU‐145 using MTT assay (average GI50<0.1 μM). Noteworthy, the BSP 7 (with vicinal‐diol functionality) was obtained when the epoxidized derivatives 4 was treated with sodium metal in dry THF.

Potential of Steroidal Alkaloids in Cancer: Perspective Insight Into Structure-Activity Relationships.

Steroidal alkaloids contain both steroidal and alkaloid properties in terms of chemical properties and pharmacological activities. Due to outstanding biological activities such as alkaloids and similar pharmacological effects to other steroids, steroidal alkaloids have received special attention in anticancer activity recently. Substituted groups in chemical structure play markedly important roles in biological activities. Therefore, the effective way to obtain lead compounds quickly is structural modification, which is guided by structure–activity relationships (SARs). This review presents the SAR of steroidal alkaloids and anticancer, including pregnane alkaloids, cyclopregnane alkaloids, cholestane alkaloids, C-nor-D-homosteroidal alkaloids, and bis-steroidal pyrazine. A summary of SAR can powerfully help to design and synthesize more lead compounds.

Chemists find path to potent anticancer compound

Ritterazine B, found in sea squirts, belongs to the class of compounds known as bis-steroidal pyrazines. This group has stronger anticancer activity than any other known natural products. But scien...

Synthesis and bioactivity of bis-steroidal pyrazine 23-deoxy-25-epi ritterostatin GN1N

Cephalostatins, ritterazines and their hybrid bis-steroidal pyrazine analogs such as 25-epi-rittereostatin GN1N show unusually high potency against a wide range of cancer cell lines. Herein, we report the synthesis and bioactivity of 23-deoxy-25-epi ritterostatin GN1N, which lacks the 23-hydroxyl group of 25-epi rittereostatin GN1N. The less oxygenated bis-steroidal pyrazine was ∼50- to 1000-fold less potent than 25-epi ritterostatin GN1N, highlighting the importance of the 23-hydroxyl group for the antiproliferative activity of the cephalostatin/ritterazine class of drugs.

Important Classes of Bioactive Alkaloids from Marine Ascidians: Structures, Isolation and Bioactivity

An intensive research effort during the last 25 years has generated an impressive number of alkaloids isolated from marine ascidians, which remain unique among marine invertebrates in that they overwhelmingly produce this kind of metabolites. The present review is focused on some major groups of ascidians' bioactive alkaloids, useful as lead structures in the search and development of new drugs or as biological probes for physiological investigation. They include the lamellarins, the ecteinascidins, bis-steroidal pyrazines and pyridoacridines. Their often extraordinary structures and significant biological activities are illustrated, reported syntheses are outlined, and structure/activity relationships are discussed where sufficient data are available to draw such conclusions. Recent discoveries concerning the current state of potential and /or development of some of them as new drugs as well as the current knowledge regarding their modes of action are also summarized.

ChemInform Abstract: Cephalostatins and Ritterazines

AbstractReview: 146 refs.

The Cephalostatins. 22. Synthesis of Bis-steroidal Pyrazine Pyrones

Cephalostatin 1 (1), a remarkably strong cancer cell growth inhibitory trisdecacyclic, bis-steroidal pyrazine isolated from the marine tube worm Cephalodiscus gilchristi, continues to be an important target for practical total syntheses and a model for the discovery of less complex structural modifications with promising antineoplastic activity. In the present study, the cephalostatin E and F rings were greatly simplified by replacement at C-17 with an α-pyrone (in 12), typical of the steroidal bufodienolides, and by a dihydro-γ-pyrone (in 16). The synthesis of pyrazine 12 from 5α-dihydrotestosterone (nine steps, 8% overall yield) provided the first route to a bis-bufadienolide pyrazine. Dihydro-γ-pyrone 16 was synthesized in eight steps from ketone 13. While only insignificant cancer cell growth inhibitory activity was found for pyrones 12 and 16, the results provided further support for the necessity of more closely approximating the natural D-F ring system of cephalostatin 1 in order to obtain potent antineoplastic activity.

Synthesis and evaluation of a fluorescent ritterazine-cephalostatin hybrid.

The cephalostatin and ritterazine natural products comprise a potent family of bis-steroidal pyrazines that display potent single-digit nanomolar inhibition of tumor cell growth. An active fluorescent ritterazine-cephalostatin hybrid probe was developed using detailed SAR data derived through total synthetic efforts. A combination of time course and confocal imaging studies indicate that this natural product family is rapidly taken up in tumor cells and localizes subcellularly within ER and surrounding the nuclear-ER interface.

The cephalostatins. 21. Synthesis of bis-steroidal pyrazine rhamnosides (1).

The synthesis of bis-steroidal pyrazines derived from 3-oxo-11,21-dihydroxypregna-4,17(20)-diene (4) and glycosylation of a D-ring side chain with α-L-rhamnose have been summarized. Rearrangement of steroidal pyrazine 10 to 14 was found to occur with boron triflouride etherate. Glycosylation of pyrazine 10 using 2,3,4-tri-O-acetyl-α-L-rhamnose iodide led to 1,2-orthoester-α-L-rhamnose pyrazine 17b. By use of a persilylated α-L-rhamnose iodide as donor, formation of the orthoester was avoided. Bis-steroidal pyrazine 10 and rhamnosides 17b and 21c were found to significantly inhibit cancer cell growth in a murine and human cancer cell line panel. Pyrazine 9 inhibited growth of the nosocomial pathogen Enterococcus faecalis.

Discovery of Hypoiodite-Mediated Aminyl Radical Cyclization Lacking a Nitrogen Radical-Stabilizing Group: Application to Synthesis of an Oxazaspiroketal-Containing Cephalostatin Analog

Synthesis of an oxazaspiroketal-containing bissteroidal pyrazine is described. The key transformation of this synthesis involves stereoselective formation of oxazaspiroketal via aminyl-radical cyclization of primary amine lacking a radical-stabilizing group by Suárez hypoiodite oxidation.

Synthesis of new symmetrical bis-steroidal pyrazine analogues from diosgenin

New symmetrical bis-steroidal pyrazine dimers that are cephalostatins/ritterazines analogues have been prepared easily from a cheap, readily available natural steroid (diosgenin). These dimers were obtained by classical, condensation of α-amino ketones in order to construct the pyrazine rings. The three dimers differ in the functionalized diosgenin: (25R)-5α,6β-dihydroxy-5α-spirosta-3-one, (25R)-4,5α-epoxy-5β-spirosta-3,6-dione and (25R)-5α-hydroxy-5α-spirosta-3,6-dione respectively.

ChemInform Abstract: Marine Natural Products-Synthetic Exercises and Biological Activity

The comparison of the biological activity in the cephalostatin and ritterazin series of marine natural products proved cephalostatin 1 to be the most active compound [1,2]. The very complex and quite unusual bis-steroidal pyrazine structure induced quite some synthetic activity in various laboratories [3±5] that culminated in a total synthesis in the group of P. Fuchs in the United States (Scheme 1) [6].

Chemistry of trisdecacyclic pyrazine antineoplastics: the cephalostatins and ritterazines.

The search for natural products of medicinal significance led the Pettit group to isolate the cephalostatins1 (from the hemichordate worm Cephalodiscus gilchristi,2 e.g. cephalostatin 1 (1), and the Fusetani team to the ritterazines3 (from the tunicate Ritterella tokioka, e.g. ritterazine B (2)), respectively. The cephalostatins and ritterazines, are a family of 45 trisdecacyclic bissteroidal pyrazines that display striking cytotoxicity against human tumors (~1 nM in the 2-day NCI 60 cell panel;4 and in some cases ~10 fM 6-day in the Purdue mini panel5), thereby ranking them among the most potent anticancer agents tested by the NCI. Computer matching at the NCI using the COMPARE program have revealed several additional compounds exhibiting similar profiles to the Cephalostatin/Ritterazine family. These compounds include OSW-16 (3) a monosteroidal saponin glycoside from the garden perennial Ornithogalum saundersiae (GI50 of 0.8 nM in the NCI 60 cancer cell line), and solamargine7 (4) (from Solanum species) as additional possible candidates for cancer therapy. OSW-1 (3) shows low toxicity to normal human pulmonary cells but encouraging activity against malignant solid tumor cells. Solamargine (4), is an active ingredient of creme Curaderm®, claimed to be 100% effective against melanomas in preliminary clinical trials without significant side effects or recurrence of cancer 10 years after treatment (Figure 1).8 Open in a separate window Figure 1 Steroidal anticancer agents.

Chemo-, regio-, and stereoselectivity of F-ring opening reactions in the cephalostatin series

In an effort to prepare unsymmetrical cephalostatin analogues with multi-functionality, we tried the route of selective opening of the spiroketal joining rings E and F. In this study, we have tested several borane complexes (like borane-9-BBN, borane-( N-tosyl)- d-valine, and borane–catechol) with some bis-steroidal pyrazine derivatives like 3, 4, and 16 aiming at opening ring-F at only one spiro-system of the dimer. Upon testing these borane reagents, satisfying results were obtained in the case of the keto-methylene 4 using the catechol–borane complex. The structures of the resulting mono-opened and also some double-opened spiro dimers have been completely confirmed. Some of the prepared compounds were tested against three cancer cell lines: HM02 (stomach cancer), HEP G2 (hepatocellular cancer), and MCF 7 (breast cancer).

Stereoselective synthesis of bis-steroidal pyrazine derivatives†

Some compounds of Cephalostatin family have shown anti-cancer activity against human cancer cell line and active intensity has close relationship with the stereochemistry of the substituted group, for example, β-OH at C-12 in compound 2 showed less promising results and the mixture 3 (α + β) showed a large enhancement of the activity compared to the compound 2. So, the work was concentrated on the synthesis of 12′α-derivatives (scheme 1) and the separable diastereomers 10 and 11 were obtained in a pure form. †Dedicated to Professor E. Winterfeldt on his 75th birthday.

Marine natural products–synthetic exercises and biological activity

Abstract

Synthesis of Cephalostatin Analogues by Symmetrical and Non-Symmetrical Routes

The synthesis of the cephalostatin-analogous bis-steroidal pyrazines 6, 27a/b and 41 by the transformation of the C2-symmetrical diketone 6 as a central precursor, as well as the direct preparation of several non-symmetrical bis-steroidal pyrazines by coupling of enamino ketones (5, 40) with vinyl azides (17a/b) is reported. Furthermore, an improved procedure for preparation of the diketone 6 described earlier is presented.

Synthesis of Cephalostatin Analogues by Symmetrical and Non-Symmetrical Routes

The synthesis of the cephalostatin-analogous bis-steroidal pyrazines 6, 27a/b and 41 by the transformation of the C2-symmetrical diketone 6 as a central precursor, as well as the direct preparation of several non-symmetrical bis-steroidal pyrazines by coupling of enamino ketones (5, 40) with vinyl azides (17a/b) is reported. Furthermore, an improved procedure for preparation of the diketone 6 described earlier is presented.

Reduction of 2-Nitro-5α-cholestan-3-one, Its Enol Tautomer and 2-Nitro-5α-cholest-2-en-3-amine Derivatives. Synthesis of Bis-Steroidal Pyrazines

Reduction of 2α-nitro-5α-cholestan-3-one (4), its enol tautomer (3a) and 3-acetylamino-2-nitro-5α-cholest-2-ene (2) was studied. The latter compound was reduced with zinc in acetic acid to 3β-acetylamino-5α-cholestan-2-one (8). The similar reaction of 3a or 4 led to 2α-amino-5α-cholestan-3-one (11a), that may be trapped as N-formyl derivative. When crude 11a was subjected to air oxidation, pyrazino[2',3':2,3;5',6':2,3]bis(5α-cholestane) (9) was obtained.