Introduction to bio-Strips

A bio-Strip of a chemical reaction is a multi-sectioned strip (Figure 1), in which the length of the sections corresponds to the “normalized cytotoxicity” (NC) of the substances:

$$NC = {n \over CC_{50}}\ (1)$$

Where n is the amount (mmol) of a given substance in a given reaction, and CC₅₀ (mmol/L) is a half-maximal cytotoxicity concentration of a given substance measured in a given cell line. Since lower CC₅₀ values reflect higher cytotoxicity, longer sections in the bio-Strip imply higher contributions of such substances to the “overall cytotoxicity” of the reaction.

The color of the sections in bio-Strips corresponds to the CC₅₀ of a given substance in a given cell line. The substance with the lowest CC₅₀ value (highest cytotoxicity) is colored red, the substance with the highest CC₅₀ value (lowest cytotoxicity) is colored green, and all the other substances are colored intermediate shades of red, orange, yellow, and green. The color distribution in the cytotoxicity scale can correspond to the percentile distribution of the CC₅₀ values or to the linear distribution of the CC₅₀ values (the former variant is more artificial but it allows producing more “colorful” bio-Strips with a higher diversity of section colors).

In Figure 1, the reaction is shown above the bio-Strips, whereas the cytotoxicity scale and explanations of the reaction name and abbreviations are shown below. Each bio-Strip is supplied with a bio-Factor (BF), which shows the change of the “overall cytotoxicity” of a particular reaction upon its course:

$$BF = {\sum NC_{out} \over \sum NC_{in}} = {\sum {n \over CC_{50}(out)} \over \sum {n \over CC_{50}(in)}}\ (2)$$

Where in and out designate the substances entering (starting materials, catalysts, solvents and other reagents) or leaving (products, byproducts and chemicals that can be recycled, such as catalysts and solvents) the reaction, accordingly. BF > 1 corresponds to an increased “overall cytotoxicity”, whereas BF < 1 corresponds to a decreased "overall cytotoxicity".

Figure 1 shows bio-Strips for six exemplary routes of synthesis of 4-nitro-1,1’-biphenyl. In these six reactions, the same starting material 2 (SM2, 1-iodo-4-nitrobenezene) and reagent (R, K₂CO₃) is used, as reflected by the first and third letters (A) in the reaction name, whereas the catalyst (CT) and solvent (S) vary: CT = Pd(OAc)₂ (A), PdCl₂ (B), or Pd(acac)₂ (C) (the second letter in the reaction name), and S = ethanol (A) or NMP (B) (the fourth letter in the reaction name). These bio-Strips readily demonstrate that catalysts A (Pd(OAc)₂) and B (PdCl₂) and solvent (A) (ethanol) are preferable from the viewpoint of the “overall cytotoxicity” of these synthetic routes.

Figure 1. bio-Strips for synthesis of 4-nitro-1,1’-biphenyl upon varying starting material 2 (SM2: 1-iodo-4-nitrobenzene (A), 1-bromo-4-nitrobenzene (B), or 1-chloro-4-nitrobenzene (C)), catalyst (CT: Pd(OAc)₂ (A), PdCl₂ (B), or Pd(acac)₂ (C)), reagent (R: Na₂CO₃ (A), K₂CO₃ (B), or Cs₂CO₃ (C)), and solvent (S: ethanol (A) or NMP (B)). The reaction is shown above the bio-Strips, whereas the cytotoxicity scale and explanations of the reaction name and abbreviations are shown below. In the bio-Strips, the length of the sections corresponds to the “normalized cytotoxicity” (NC) of the substances, and the color of the sections corresponds to the CC₅₀ value of a given substance in a given cell line (in this case - CaCo-2). Note that here, the cytotoxicity scale is colored in accordance with the percentile distribution of the CC₅₀ values. bio-Factors (BFs) are provided below the bio-Strips. Only 6 out of 36 bio-Strips are shown for clarity.

In addition to BFs, cytotoxicity potentials for each bio-Strip are calculated: CP_i (initial cytotoxicity potential, or CP of the substances entering the reaction); CP_f (final cytotoxicity potential, or CP of the substances leaving the reaction), and CP_{f_rel} (relative final cytotoxicity potential, or CP of the substances leaving the reaction except for the target product). In essence, CPs show the quantity of the liters of the cell media that can be “poisoned” by the corresponding substances:

$$CP_i = {\sum NC_{in}}\ (3)$$ $$CP_f = {\sum NC_{out}}\ (4)$$ $$CP_{f\_rel} = {\sum NC_{out} - NC_{product}}\ (5)$$

In the case of CPs, lower values correspond to reactions with lower “overall cytotoxicity”. Thus, by looking at the initial and final CPs of various synthetic routes for a particular target product, we can suggest the safer ones without looking at CC₅₀ values of the individual substances involved.

Click here to build bio-Strips for your own chemical processes using your own data on biological activity.

A detailed step-by-step description of the procedure is provided in the Manual tab.