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Revamped Intro, original on topoisomerase inhibitors page:

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Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which are broken into two broad subtypes: topoisomerases I and  topoisomerases II.[1][2][3] Topoisomerases mediate the cleavage of single and double stranded DNA to relax supercoils, untangle catenanes, and condense chromosomes in eukaryotic cells.[1][2][3] Topoisomerases are involved in the process of cellular reproduction and allow for the packaging of DNA.[2] Topoisomerase inhibitors influence these essential cellular processes through their interactions with topoisomerases. Some topoisomerase inhibitors prevent topoisomerases from performing DNA strand breaks while others, deemed topoisomerase poisons, associate with topoisomerase/DNA complexes and prevent the re-ligation step of the topoisomerase mechanism. Topoisomerase/DNA/inhibitor complexes are cytotoxic agents, as the unrepaired single and double stranded DNA breaks that they cause can lead to apoptosis and cell death (Biochem textbook, intro source).[2][3] Because of this ability to induce apoptosis, topoisomerase inhibitors have gained interest as therapeutics against infectious and cancerous cells.

History:

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General:

Studies on antibiotic and anticancer agents since the mid to late 20th century have illuminated the existence of numerous unique families of both TopI and TopII inhibitors, with1960s alone resulting in the discovery of the camptothecin, anthracycline and epipodophyllotoxin classes.[4] Topoisomerase inhibitor classes have been derived from a wide variety of disparate sources, with some being natural products first extracted from plant[5](***epipodophyllotoxin source***) or bacterial[6][7] samples, while others possess purely synthetic, and often accidental, origins.[8][9] After their initial discoveries, the structures of these classes have been fine tuned through the creation of derivatives in order to make safer, more effective, and are more easily administered variants.[5][8][10][11] The first members of some topoisomerase inhibitor classes, such as the indenoisoquinolines and the quinolones, showed limited potency as antibiotics or anticancer drugs when they were first discovered, but their effectivity has since been greatly enhanced as their derivatives have been perfected.[8][10] In 1976, the paper that detailed the discovery of the bacterial topoisomerase DNA gyrase discussed its inhibition when introduced to coumarin and quinolone class inhibitors, sparking greater interest in topoisomerase targeting antibiotic and antitumor agents.[3][12] Topoisomerase inhibitors have been used as important experimental tools that have contributed to the discovery of some topoisomerases themselves, as the quinolone nalidixic acid helped elucidate the bacterial TopII proteins it binds specifically to.[8] Currently...*************

NEW AND IMPROVED:

Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which are broken into two broad subtypes: type I topoisomerases (TopI) and type II topoisomerases (TopII).[13][14][15] Topoisomerases play important roles in cellular reproduction and DNA organization, as they mediate the cleavage of single and double stranded DNA to relax supercoils, untangle catenanes, and condense chromosomes in eukaryotic cells.[13][14][15] Topoisomerase inhibitors influence these essential cellular processes. Some topoisomerase inhibitors prevent topoisomerases from performing DNA strand breaks while others, deemed topoisomerase poisons, associate with topoisomerase/DNA complexes and prevent the re-ligation step of the topoisomerase mechanism.[15] These topoisomerase/DNA/inhibitor complexes are cytotoxic agents, as the un-repaired single and double stranded DNA breaks that they cause can lead to apoptosis and cell death.[14][15] Because of this ability to induce apoptosis, topoisomerase inhibitors have gained interest as therapeutics against infectious and cancerous cells.

History:

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(EGB): In the 1940s, great strides were made in the field of antibiotic discovery by researchers like Albert Schatz, Selman A. Waksman, and H. Boyd Woodruff that marked the beginning of significant effort being allocated to the search for novel antibiotics.[16][17][18] Studies searching for antibiotic and anticancer agents in the mid to late 20th century have illuminated the existence of numerous unique families of both TopI and TopII inhibitors, with the 1960s alone resulting in the discovery of the camptothecin, anthracycline and epipodophyllotoxin classes.[19] Knowledge of topoisomerase inhibitors predates the discovery of the first topoisomerase (E. coli omega protein, a TopI) by Jim Wang in 1971.[20] In 1976, Gellert et al. detailed the discovery of the bacterial TopII DNA gyrase and discussed its inhibition when introduced to coumarin and quinolone class inhibitors, sparking greater interest in topoisomerase-targeting antibiotic and antitumor agents.[15][21] Topoisomerase inhibitors have been used as important experimental tools that have contributed to the discovery of some topoisomerases, as the quinolone nalidixic acid helped elucidate the bacterial TopII proteins it binds to.[22] Topoisomerase inhibitor classes have been derived from a wide variety of disparate sources, with some being natural products first extracted from plants (camptothecin[23], etoposide[24]) or bacterial samples (doxorubicen[25], indolocarbazole[26]), while others possess purely synthetic, and often accidental, origins (quinolone[22], indenoisoquinoline[27]) After their initial discoveries, the structures of these classes have been fine tuned through the creation of derivatives in order to make safer, more effective, and are more easily administered variants.[23][22][27][28] Currently, topoisomerase inhibitors hold a prominent place among antibiotics and anticancer drugs in active medical use, as inhibitors like doxorubicen[25] (anthracycline, TopII inhibitor), epotoside[24] (TopII inhibitor), ciprofloxaxin[29] (fluoroquinolone, TopII inhibitor), and irinotecan[30] (camptothecin derivative TopI inhibitor) were all included on the 2019 WHO Model List for Essential Medicines.[31]

TopI Inhibitors:

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Camptothecins:

  • Camptothecin was first derived from the tree Camptotheca acuminata, native to southern China.[32] It was isolated in a USDA led search for cortisone precursors in the late 1950s and its anticancer activity explored in the early 1960s by John Hartwell and his lab at the Cancer Chemotherapy National Service Center.[5] Clinical trials during the 1970s converted camptothecin into its sodium salt in order to increase its solubility for injection, but in this form it proved to be less effective at treating cancer and came with adverse health effects.[33] It was not until 1985 that Hsiang et al. deduced by utilizing topoisomerase relaxation assays that the anti-tumor activity of camptothecin was due to its topoisomerase I inhibitory activity.[34] "which demonstrated evidence of the selective poisoning of Topoisomerase in vitro" This ushered in the development of camptothecin derivatives, and there are now three currently FDA approved derivatives: topotecan, irinotecan, and Belotecan.[33]
Inhibitors of Topoisomerase I were first based on Camptothecin, which demonstrated evidence of the selective poisoning of Topoisomerase in vitro; however, clinical trials showed limited effectiveness due to toxic effects regarding the pharmacological characteristics.  Alternatively,  the discovery of Camptothecin led to the synthesis of three currently FDA approved derivatives: topotecan, irinotecan, and Belotecan.

Non-Camptothecins:

  • Cushman et al. (1978) details their discovery of the first indenoisoquinoline, indeno[1,2-c]isoquinoline (NSC 314622), which was made accidentally in an attempt to synthesize nitidine chloride, an anticancer agent that does not inhibit topoisomerases.[10][35][36] Research on the anticancer activity of indenoisoquinoline ceased until the late 90s as interest grew for camptothecin class alternatives.[10] Since then, work on developing effective derivatives have been spearheaded by researchers like Dr. Mark Cushman at Purdue University and Dr. Yves Pommier at the National Cancer Institute.[10][37][38] As of 2015, Indotecan (LMP-400) and Indimitecan LMP-776, derivatves of indeno[1,2-c]isoquinoline, were in Phase I clinical trials.[39]
  • The first member of the indolocarbazole family of topoisomerase inhibitors, BE-13793C, was discovered in 1991 by Kojiri et al. It was found to be produced by a streptomycete similar to Streptoverticillium mobaraense, and DNA relaxation assays revealed that BE-13793C is capable of inhibiting both topoisomerases I and II.[7] In 1992, Yamashita et al. created KT6006, KT5028, TopI inhibitory derivatives of the indolocarbazole antibiotic K252a.[40] Another general source[41]

Shift in Mechanistic Understanding:

Cushman et al. (2000) mentions that due to a lack of observed DNA unwinding in experiments involving camptothecin and indenoisoquinoline, they believed that these inhibitors likely did not function through a mechanism involving DNA intercalation.[10] This hypothesis has been disproved, as X-ray crystallography has allowed for the visualization of TopI inhibitor DNA intercalation.[9] 

Non-Camptothecins:

(AD) Despite the clinical success of the many CPT derivatives, they require long infusions, have low water solubility, and possess many side effects such as temporary liver dysfunction, severe diarrhea, and bone marrow damage.[42] Additionally, there has been an increase in observed single point mutations that have shown to prompt TOP1 resistance to Camptothecin.[43] Therefore, three clinically relevant non-Camptothecin inhibitors, indenoisoquinoline, phenanthridines, and indocarbazoles, are currently being considered by the FDA as possible chemotherapies.[44] Among the non-Camptothecin inhibitors, indolocarbazoles have shown the most promise. These inhibitors have unique advantages compared with the Camptothecin. First, they are more chemically stable due to the absence of the lactone E-ring.[44] Second, indolocarbazoles attach to TOP1 at different section of the DNA. Third, this inhibitor expresses less reversibility than Camptothecin.[45] Therefore, they require infusion times because the Top I and inhibitor complex is less likely to dissociate.[44][45] Currently, several other indolocarbazoles are also undergoing clinical trials.[46] Other than indocarbazoles, Topovale (ARC-111) is considered one of the most clinically developed phenanthridine. They have been promising in fighting colon cancer, but limited effectiveness against breast cancer.[47]

(EGB) The first member of the indolocarbazole family of topoisomerase inhibitors, BE-13793C, was discovered in 1991 by Kojiri et al.[48]**** It was found to be produced by a streptomycete similar to Streptoverticillium mobaraense, and DNA relaxation assays revealed that BE-13793C is capable of inhibiting both TopI and TopII.[48] Soon after, more indolocarbazole variants were found with TopI specificity.[49]

Cushman et al. (1978) details their discovery of the first indenoisoquinoline, indeno[1,2-c]isoquinoline (NSC 314622), which was made accidentally in an attempt to synthesize nitidine chloride, an anticancer agent that does not inhibit topoisomerases.[50][45][51] Research on the anticancer activity of indenoisoquinoline ceased until the late 90s as interest grew for camptothecin class alternatives.[50] Since then, work on developing effective derivatives has been spearheaded by researchers like Dr. Mark Cushman at Purdue University and Dr. Yves Pommier at the National Cancer Institute.[50][52][53] As of 2015, Indotecan (LMP-400) and Indimitecan LMP-776, derivatves of indeno[1,2-c]isoquinoline, were in Phase I clinical trials for the treatment of solid tumors and lymphomas.[54] 

To circumvent these limitations, Dr. Mark Cushman at Purdue University and Dr. Yves Pommier at the National Cancer Institute developed The non-camptothecin family of indenoisoquinoline inhibitors of Top1 has the potential to circumvent some of these shortcomings. In contrast to the camptothecins, the indenoisoquinolines are: 1) chemically stable in blood, 2) inhibitors of Top1 cleavable complexes at distinct sites, 3) not substrates of membrane transporters, and 4) more effective as anti-tumor agents in animal models.

TopII Inhibitors:

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Intercalating Poisons:

Anthracyclines:

  • Doxorubicin and its precursor daunorubicin were first isolated from Streptomyces peucetius in the 1960s and their derivatives have since grown into the anthracycline topoisomerase II inhibitor family.[11][6] Daunorubicin was discovered independently by two separate labs in the early 1960s.[55]

It is commonly used in combination with other chemotherapeutic agents.[6]

Antitumor antibiotics research began in 1940 with the Waksman Woodruff discovery of actinomycin A from Actinomyces Antibioticus[55]

Do more digging on actinomycin D, mitoxantrone, mAMSA and amonafide and ellipticine

Non-Intercalating Poisons:

The first quinolone was discovered in1963 by the company Sterling Drug (now owned by Sanofi) as an impurity collected while manufacturing chloroquine, an antimalarial drug.[56][57] This impurity was used to develop nalidixic acid, which was made clinically available in 1964.[56] Its gram negative activity, novel structure and mechanism of activity showed promise for the quinolone class of inhibitors but its small spectrum of activity and ineffectively against streptoccoci and anaerobes relegated it to be solely used to treat urinary tract infections.[56][57][8] The first member of the fluoroquinolone subclass, norfloxavin, was discovered by Koga et al. in 1978.[57] Norfloxacin effects a broader spectrum of bacteria and possesses higher anti-gram negative potency than standard quinolones and shows some anti-gram positive effects.[8][57] Since the creation of norfloxacin, numerous fluoroquinolone derivatives have been developed, including ciprofloxacin and levofloxacin which are often listed as part of the top 100 most proscribed drugs in North America.[8] Fluoroquinolones have proven to be easier to synthesize than most antibiotics derived from fermentation, are able to be orally administered, and are effective at clinically achievable doses and on a wide array of microbial targets***.[8]

Shift in Mechanistic Understanding:

The, since disproven, Shen et al. (1989) model of quinolone inhibitor binding proposed that, in each inhibitor-DNA-DNAgyrase complex, four quinolone molecules associate with one another via hydrophobic interactions and form hydrogen bonds with the bases of separated, single stranded segments of DNA.[8][58][59] Shen et al. based their hypothesis on observations regarding the increased affinity and site specificity of quinolone binding to single stranded DNA compared to relaxed double stranded DNA.[58] A modified version of the Shen et al. model was still regarded as a likely mechanism of in the mid 2000s,[8] but X-ray crystallography-based models of inhibitor-DNA-TopII complex stable intermediates developed in the late 2000s and early 2010s have since contradicted this hypothesis.[60][59] This newer model suggests that two quinolone molecules intercalate at the two DNA nick sites created by TopIIA, aligning with a hypothesis proposed by Leo et al. (2005).[61][59]

  • Quinolone also inhibits bacterial DNA gyrase and top IV (selective to bacterial Tops), Blocks re-ligation step, 1962: nalidixic acid - led to the development of fluoroquinolones like ciprofloxacin (Cipro) - can fight anthrax, take that bioterrorism![2]
  • 1963- Began with the discovery of naphthyridine agent and nalidixic acid first published by Sterling Drug[57][56]
  • Feud between Sterling Drug and Imperial Chemical Industries[56]
  • Discovered as an impurity in a batch of the antimalarial chloroquine during manufacturing, became nalidixic acid[56]
  • nalidixic acid limited to only treating UTI[57]
  • 1964- nalidixic acid is clinically introduced[56]
  • Gram negative activity, unique, simple structure[57]
  • Gram negative activity, limited range of effectivity[56]
  • Limited spectrum of activity against streptoccoci and anaerobes[57]
  • 2-Pyrodones, switching around nitrogens in the double ring structure[57]
  • 1978- C-6-Fuoroquinolones discovered to be order of magnitude more active than the other gram negative treatments that came before it found to be an effective treatment for a broader spectrum of bacterial targets by Koga and coworkers in Kyorin Japan, norfloxacin is the first member of the fluoroquinolones[57] Also possessed some activity against gram positive bacteria[8]
  • norfloxacin- simple structure easy synthesis compared to a lot of fermentation derived antibiotics[8]
  • along with N-methyl analog pefloxacin, had low active blood levels and not that effective against gram positive[8]
  • 1980s- Fluoroquinolones, fluorine substitution on sixth carbon of quinolone or 1,8-naphthyridone and basic amino heterocyclic group at seventh position[56]
  • 20 years later it was discovered that 6-fluorine moiety is actually not necessary for effective quinolones- revealed at 37th InterscienceConference on Antimicrobial Agents and Chemotherapy (ICAAC)[57]
  • 80% of MRSA also resistant to ciprofloxacin[57]
  • Fluoroquinolones: orally and parenterally active broad spectrum, clinically achievable doses, easy synthesis [8]
  • Two dozen agents in use institutionally and office practice[8]
  • In top 200 of most frequently proscribed medications[8]
  • Ciprofloxacin and Levofloxacin among 100 most frequently prescribed in North America.[8]
  • Gatefloxacin and Moxifloxacin enhanced Gram Positive Activity[8]
  • Trovafloxacin- anti-anerobic coverage[8]
  • ******nalidaxic acid helped discover the bacterial topoisomerases that it targeted [8] *****(CAN I CONNECT THIS TO NOVOBIOCIN USE IN DISCOVERY OF DNA GYRASE?[3][12])
Quinolones

(AD) The most common antibiotics used to treat bacterial infections in humans are quinolones, which treat illness such as urinary infections, skin infections, sexually transmitted diseases, tuberculosis and some anthrax infections.[62][63][64] The effectiveness of quinolones is proposed to be from chromosome fragments, which initiate the accumulation of reactive oxygen species that leads to apoptosis. [62] Quinolones can be divided into four generations:

  1. First Generation: Nalidixic acid[65]
  2. Second Generation: Cinoxacin, Norfloxacin, Ciprofloxacin[65]
  3. Third Generation: Levofloxacin, Sparfloxacin[65]
  4. Fourth Generation: Moxifloxacin[65]

(EGB) The first generation quinolone was discovered in 1962 by George Lesher and his co-workers at Sterling Drug (now owned by Sanofi) as an impurity collected while manufacturing chloroquine, an antimalarial drug.[66][67][68](Vsource)********* This impurity was used to develop nalidixic acid, which was made clinically available in 1964.[66] Its gram negative activity, novel structure, and mechanism showed promise but it was relegated to solely treat urinary tract infections because of its small spectrum of activity.[66][67][65] (AD) The newer generation of drugs are classified as fluoroquinolones due to the addition of a fluorine and a methyl-piperazine, which allows for improved gyrase targeting (TopII).[64] (EBG) It is hypothesized that this added fluorine substituent aids in base stacking during fluoroquinolone intercalation into TopII cleaved DNA by altering the electron density of the quinolone ring.[69] Fluoroquinolones have proven to be easier to synthesize than most antibiotics derived from fermentation, and are effective on a broad spectrum of microbial targets.[65] (Previously: are able to be orally administered, and are effective at clinically achievable doses) The first member of the fluoroquinolone subclass, norfloxacin, was discovered by Koga and his fellow researchers and Kyorin in 1978.[67] It was found to possess higher anti-gram negative potency than standard quinolones, and showed some anti-gram positive effects.[65] It exhibited both low blood serum levels and poor tissue penetration abilities and was overshadowed by the development of ciprofloxacin, a fluoroquinolone with a superior spectrum of activity.[68](Vsource)*********

(AD) Currently, the U.S. Food and Drug Administration (FDA) has updated the public on eight new-generation fluoroquinolones: Moxifloxacin, delafloxacin, ciprofloxacin, ciprofloxacin extended-release, Gemifloxacin, levofloxacin, and ofloxacin.[70] It was observed that the new fluoroquinolones can cause hypoglycemia, high blood pressure, and mental health effects such as agitation, nervousness, memory impairment and delirium.[71][72]

Although quinolones success as antibiotics, their effectiveness is limited due to accumulation of small mutations and multidrug efflux mechanisms, which pump out unwanted drugs out of the cell.[64] In particular, smaller quinolones have shown to bind with high affinity in the multidrug efflux pump in Escherichia coli and Staphylococcus aureus.[73][74] [75] Despite quinolones ability to target Top II, they can also inhibit Top IV based on the organisms and type of quinolone[64]. Additionally, the discovery of mutations in the GyrB region is hypothesized to cause quinolone-based antibiotic resistance.[64][76] Specifically, the mutations from aspartate (D) to asparagine (N), and Lysine (K) to glutamic acid (E) are believed to disrupt ionic interactions, leading to some loss of tertiary structure. [64][76]

(EGB) Mechanically, the since disproven, Shen et al. (1989) model of quinolone inhibitor binding proposed that, in each inhibitor-DNA-DNAgyrase complex, four quinolone molecules associate with one another via hydrophobic interactions and form hydrogen bonds with the bases of separated, single stranded segments of DNA.[65][77][69] Shen et al. based their hypothesis on observations regarding the increased affinity and site specificity of quinolone binding to single stranded DNA compared to relaxed double stranded DNA.[77] A modified version of the Shen et al. model was still regarded as a likely mechanism of action in the mid to late 2000s,[78][65]******** but X-ray crystallography-based models of inhibitor-DNA-TopII complex stable intermediates developed in 2009 have since contradicted this hypothesis.[79][69] This newer model suggests that two quinolone molecules intercalate at the two DNA nick sites created by TopII, aligning with a hypothesis proposed by Leo et al. (2005).[80][69][68] (Vsource)

[81]


[78]

Lists fluoroquinolone as non-intercalating

[68]

George Lesher

Shift mentioned

THIS IS WHAT AMEY ALREADY HAS ON STRUCTURE:
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(AD) The most common antibiotics used to treat bacterial infections in humans are quinolones, which treat illness such as urinary infections, skin infections, sexually transmitted diseases, and tuberculosis.[82] The effectiveness of Quinolones against infectious agents is proposed to be from chromosome fragments, which initiate the accumulation of reactive oxygen species that leads to apoptosis. [82] Quinolones can be divided into four generations:

First Generation: Nalidixic acid

Second Generation: Cinoxacin, Norfloxacin, Ciprofloxacin, and Ofloxacin

Third Generation: Levofloxacin, Sparfloxacin

Fourth Generation: Moxifloxacin

The old-generation (one and two) include quinolones such as Cinoxacin, Norfloxacin, Ciprofloxacin, and Ofloxacin.[83]The newer generation (three and four) include Levofloxacin, Sparfloxacin, and Moxifloxacin drugs.[84] New generations drugs are classified as fluoroquinolones due to the addition of a fluorine and a methyl-piperazine, which allows for improved gyrase targeting (top II).[83] Fluoroquinolones are promising in fighting anthrax infections and used against agents of bioterrorism.[83][84] Currently, the  U.S. Food and Drug Administration (FDA) has approved eight new-generation fluoroquinolones: Moxifloxacin, delafloxacin, ciprofloxacin, ciprofloxacin extended-release, Gemifloxacin, levofloxacin, and ofloxacin.[85] Despite these quinolones success as antibiotics, their effectiveness are limited due to accumulation of small mutations and multidrug efflux mechanisms, which pumps out unwanted drugs out of the cell through through a general TolC channel.[84] In particular, smaller quinolones have shown to bind with high affinity to AcrB of the multidrug efflux pump in Escherichia coli and Staphylococcus aureus.[86][87] [88]Furthermore, the FDA include described the following side effects: hypoglycemia, high blood pressure, and mental health effects such as agitation, nervousness, memory impairment and delirium.[89][90]

Despite quinolones function to target Top II, they can also inhibit Top IV  based on 1) the organisms 2) type of quinolone 3) mutations in GyrA and GyrB.[84] It's hypothesized the mutations in the GyrB region could cause quinolone-based antibiotic resistance. In particular, the mutations from aspartate (D) to asparagine (N), and Lysine (K)  to glutamic acid (E) are believed to disrupt ionic interactions, leading to some loss of tertiary structure. [84][91] ***One such mutation involves the conversion of a positively charged amino acid residue in the ParE subunits of TopIV close to the 7 position of a bound quinolone to a negatively charged glutamate, a change that does not hinder the effectivity greatly of quinolones with basic substituents at position 7, such as moxifoxacin[60]****

Structure:

A quinolone core has one nitrogen in its two six membered ring system, attached to a varying substituent, a carboxylic acid substituent(position 3), and a keto substituent (position 4)[56]. New generations drugs are classified as fluoroquinolones due to the addition of a fluorine (at position 6) and a substituent with a methyl-piperazine component (at position 7), which allows for improved gyrase targeting (top II). In the currently understood quinolone binding pocket, the fluorine of fluoroquinolones...******* Among quinolone and fluoroquinolone derivatives, a considerable amount of variation occurs at the position C7, which typically rests near positively charged amino acid residues while intercalating.[60]

1,8-naphthyridone core has two nitrogens in it's two six membered ring system[56]

1,8-naphthyridone core is sometimes called 8-azaquinolone[56]

  • Nitrogen position in the two rings of quinoline is important for specificity.[57]
  • Quinolines usually constructed with nitrogen at position 1[57]
  • Second nitrogen at the 5 position: 2-pyridopyrimidones family[57]

Structural Basis:[60]

Structure Insight--Breif Communication:[59]

Paper:[92]

Quinazolinediones- top IV, gram positive activity, new class

Resume of Structure/Activity Relationships in overarching paper[8]

Structures

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Camptothecin

Camptothecin is an alkaloid composed of five rings, one delta lactone ring, two benzene rings, one delta lactam, and one pyrrolidine ring and three variable substituent sites.[9][5] When binding to the Top1/DNA complex, the E ring of camptothecin is positioned close to the Top 1 active site.[9]

CPT inhibition is ***sequence-specific*** as it intercalates with a thymine (T) at the −1 position and a guanine (G) at the +1 position on the scissile strand[39]

10-hydroxy-CPT is more active than CPT [5]

***Distinguish between lactone and open form

Topotecan

Irinotecan

What is the methodology of the creation of more active camptothecin derivatives? Indenoisoquinoline

The core structure of indenoisoquinoline is typically composed of four rings (two benzines, one cyclopentadienone, one delta-lactam). Some possess a fifth ring, like NSC314622 which has an additional non-aromatic five membered ring containing two oxygens. There are five regions where ring substituents vary depending on the type of indenoisoquinoline. [9] ***The carbonyl on the C ring rests towards the minor groove side of the binding pocket and a bidentate interaction is formed with both of the arginine 364 side chain nitrogens***.[9] ***NSC314622- methoxy group in the R1 position***.[9] MJ238: butyl-carboxylic acid at R3 substituent that enters the major groove and reaches towards asparagine 352 and alanine 351.[9] Particularly cytotoxic indenoisoquinolines possess an amino alkyl side chain on their nitrogen atom.[10]

  • DNA cleavage patterns different from camptothecin[10]
  • DNA breaks by first indenoisoquinoline were more stable than camptothecin[10]

Indolocarbazole

The core structure of indolocarbazole possesses six rings, three benzines, two cyclic pyrrols, one maleimide, many have glucose substituent.[9]

Chemical Shortcomings of Camptothecin:

Camptothecin, indenoisoquinoline, and indolocarbazole all possess a free electron pair positioned close to Arginine 364 when they enter their DNA intercalation/protein binding site.[9] However, camptothecin is inferior to indenoisoquinoline and indolocarbazole due to its lactone ring opening instability and rapid top I binding reversibility.[10] How are indolocarbazole and indenoisoquinoline an improvement from camptothecin?

Phenanthridine****** 

Top1 then religates the cleaved strand to reestablish duplex DNA.  Treatment with Top1 inhibitors stabilize the intermediate cleavable complex, preventing DNA relegation, and inducing lethal DNA strand breaks. ***During replication, events where the replication fork meets these stable intermediates are thought to be a cause of double strand breaks.[93]*** Topo1 inhibitors function by forming a ternary complex with Topo1-DNA and are able to stack between the base pairs that flank the cleavage site due to their planar structure. Normal cells have multiple DNA checkpoints that can initiate the removal of these stabilized complexes, preventing cell death. In cancer cells, however, these checkpoints are typically inactivated, making them selectively sensitive to Topo1 inhibitors.  Noncamptothecins, such as indenoisoquinolines and indolocarbazoles, also associate with Topo1 itself, forming hydrogen bonds with residues that confer resistance to camptothecin. Indenosioquinolines and indolocarbazoles also lack the lactone ring present in camptothecin, making them more chemically stable and less prone to hydrolysis at biological pH.

In contrast to the camptothecins, the indenoisoquinolines are: 1) chemically stable in blood, 2) inhibitors of Top1 cleavable complexes at distinct sites, 3) not substrates of membrane transporters, and 4) more effective as anti-tumor agents in animal models. The preclinical and IND package filed with the US Food and Drug Administration along with complete GMP production supporting the lead molecule are components of the published and non-published information covered by the license agreement with Purdue Research Foundation the National Cancer Center and Linus Oncology, Inc.[citation needed]

SECTION FROM ORIGINAL ARTICLE:

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Human DNA topoisomerase I (Top1) is an essential enzyme that relaxes DNA supercoiling during replication and transcription. Top1 generates DNA single-strand breaks that allow rotation of the cleaved strand around the double helix axis. Top1 also re-ligates the cleaved strand to reestablish intact duplex DNA. The Top1-DNA intermediates, known as cleavage complexes, are transient and at low levels under normal circumstances. However, treatment with Top1 inhibitors, such as the camptothecins, stabilize the cleavable complexes, prevent DNA religation and induce lethal DNA strand breaks. Cancer cells are selectively sensitive to the generation of these DNA lesions.[citation needed]

Top1 is a validated target for the treatment of human cancers. Camptothecins are among the most effective anticancer agents recently introduced into clinical practice. In this regard, the camptothecin derivative topotecan (Hycamtin) is approved by the U.S. FDA for the treatment of ovarian and lung cancer. Another camptothecin derivative irinotecan (CPT11) is approved for the treatment of colon cancer.[citation needed]

There are, however, certain clinical limitations of the camptothecin derivatives. These include: 1) spontaneous inactivation to a lactone form in blood, 2) rapid reversal of the trapped cleavable complex after drug removal, requiring prolonged infusions, 3) resistance of cancer cells overexpressing membrane transporters, and 4) dose-limiting side effects of diarrhea and neutropenia.[citation needed]

To circumvent these limitations, Dr. Mark Cushman at Purdue University and Dr. Yves Pommier at the National Cancer Institute developed the non-camptothecin family of indenoisoquinoline inhibitors of Top1. In contrast to the camptothecins, the indenoisoquinolines are: 1) chemically stable in blood, 2) inhibitors of Top1 cleavable complexes at distinct sites, 3) not substrates of membrane transporters, and 4) more effective as anti-tumor agents in animal models. The preclinical and IND package filed with the US Food and Drug Administration along with complete GMP production supporting the lead molecule are components of the published and non-published information covered by the license agreement with Purdue Research Foundation the National Cancer Center and Linus Oncology, Inc.[citation needed]

Linus Oncology has licensed the intellectual property that covers the development of these and related indenoisoquinoline derivatives. Phase I Study in Adults With Relapsed Solid Tumors and Lymphomas is ongoing (2012).[citation needed]

Indenoisoquinolines (green) form a ternary complexes of Top1 (brown) and DNA (blue) (Pommier et al.) and act as interfacial inhibitors.[citation needed]

There are several advantages of these novel non-camptothecin Top1 inhibitors as compared to the FDA-approved camptothecin analogs:[citation needed]

They are synthetic and chemically stable compounds

The Top1 cleavage sites trapped by the indenoisoquinolines have different genomic locations, implying differential targeting of cancer cell genomes

The Top1 cleavage complexes trapped by indenoisoquinolines are more stable, indicative of prolonged drug action

The indenoisoquinolines are seldom or not used as substrates for the multidrug resistance efflux pumps (ABCG2 and MDR-1)

Based on these highly favorable characteristics, two indenoisoquinoline derivatives (from a series of > 400 molecules), indotecan (LMP400; NSC 743400) and indimitecan (LMP776; NSC 725776) are presently under evaluation in a Phase I clinical trial being conducted at the National Cancer Institute for patients with relapsed solid tumors and lymphomas.


Anthracycline structure:

Anthracyclines have a core of four hexane rings, a central two neighboring quinone (C) and hydroquinone (B) rings that lie between two benzines. Ring A is connected to two substituents, a daunosamine sugar and a carbonyl with a varying side chain.[11]

There are four main anthracyclines in medical use, doxorubicin, daunorubicin, epirubicin (the stereoisomer of doxorubicin) and idarubicin (a daunorubicin derivative).[11] Idarubicin is able to pass through cell membranes easier than daunorubicin and doxorubicin because it does not possess a D-ring methoxy group or a methoxy group connected to its carbonyl substituent, making it more lipophilic.[11][94] It is hypothesized that doxorubicin, which possesses both of these methoxy group substituents, can form hydrogen bonding aggregates with itself on the surface of phospholipid membranes, further reducing its ability to enter cells.[94] The harmful oxygen free radical generation associated with the use of doxorubicin and other anthracyclines stems from their quinone moiety undergoing redox reactions mediated by oxido-reductases.[11][6]  These redox reactions result in the formation of a superoxide anion, hydrogen peroxide, and a hydroxyl radical.[6] The mitochondrial electron transport chain pathway containing NADH hydrogenase is a potential instigator of these redox reactions and the reactive oxygen species produced by this interaction can interfere with cell signaling pathways.[11][6]

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